Anti-TL1A Antibodies and Methods of Use Thereof

Abstract

The present invention discloses an isolated antibody that specifically binds to TL1A and contains a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), the sequences of CDR-H1, CDR-H2, and CDR-H3 of the TL1A-VH sequence selected from the group consisting of the sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, SEQ ID NO: 120; and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 364,559, filed May 11, 2022; U.S. Provisional Application No. 63 / 371,697, filed Aug. 17, 2022; and U.S. Provisional Application No. 63 / 495,762, filed Apr. 12, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention relates to antibodies that specifically bind to TL1A. The present invention further relates to antibodies that bind to TL1A and p40. The present invention further relates to monovalent antibodies that specifically bind to TL1A. The present invention also relates to related molecules, such as nucleic acids encoding such antibodies, compositions, and related methods, such as methods for producing and purifying such antibodies, and their use in diagnostics and therapeutics.

[0003] Incorporation by Reference of Sequence Listing The XML - formatted sequence listing, named 42065_Sequence_Listing.xml, created on May 4, 2023, and submitted to the Patent Center of the United States Patent and Trademark Office, which is 344 KB, is incorporated herein by reference.

Background Art

[0004] Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis (UC), are chronic inflammatory disorders that affect approximately 1.6 million people in the United States and approximately 2.5 - 3 million people in Europe. Treatment recommendations for inducing remission in moderately to severely active UC patients include appropriate doses of oral corticosteroids, the tumor necrosis factor inhibitor (TNFi) infliximab (monotherapy or in combination with azathioprine), adalimumab, ustekinumab, golimumab, biological therapies such as vedolizumab, an integrin receptor antagonist, and tofacitinib, an oral small - molecule Janus kinase inhibitor. 17However, non-responsiveness and lack of response to treatment have been observed in UC, and thus, the development of novel therapies for UC and IBD still represents an unmet clinical need. 18 。

[0005] Various elements of the mucosal immune system, including epithelial cells, innate and adaptive immune cells, cytokines, and chemokines, contribute to the pathogenesis of IBD. 19 。One of the immune system components involved in the pathogenesis of IBD is TNF-like ligand 1A (TL1A or tumor necrosis factor superfamily member 15 (TNFSF15)).

[0006] Tumor necrosis factor (TNF)-like ligand 1A (TL1A) is a member of the TNF family of cytokines, also known as TNFSF15. TL1A is the only ligand for its receptor, death receptor 3 (DR3, also known as TNFRSF25). TL1A expression in antigen-presenting cells (monocytes, macrophages, dendritic cells) and DR3 expression in effector cells (T cells, NK, and NKT cells) are highly dependent on pro-inflammatory states. 20~22 。In vivo and in vitro evidence supports the co-stimulatory role of the TL1A / DR3 pathway in T cells and in enhancing effector cell function, inflammatory cell expression, and cytokine secretion. Furthermore, this pathway is involved in the regulation of Th1, Th2, and Th17 helper T responses to pathogens and NK and NK-T cell responses in immune-mediated diseases. 21、23~26 。

[0007] Studies of DR3- or TL1A-deficient mice or mice treated with anti-TL1A antibodies demonstrate the role of this pathway in several autoimmune disease models, such as IBD, asthma, multiple sclerosis, and arthritis. 25、27~28 。

[0008] In addition, much of the literature from studies involving non-clinical species and humans indicates that TL1A is most significantly associated with the pathophysiology of inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD). That is, many genome-wide association studies have associated several polymorphisms of the TL1A gene with UC and CD in patient populations of Japanese, European, and Asian origin. 29~33 .

[0009] In addition, IBD tissues that have undergone human inflammation express high levels of TL1A and DR3, and several independent laboratories have demonstrated that blockade with an antibody to TL1A prevents or attenuates intestinal inflammation in several IBD model mice. 22、24、26、34~39 .

[0010] The exact cause of IBDs (e.g., CD and UC) is unknown, but inhibition of pro-inflammatory cytokines and adhesion molecules has been shown to provide some therapeutic benefit. However, despite current medical therapies, most CD patients may ultimately require surgery, and repeated resections can lead to short bowel syndrome and ultimately, lifelong parenteral nutrition and its associated complications for the patient. Therefore, there has been a long-standing unmet need for more robust treatment for CD patients. Furthermore, there has been a long-standing unmet need for new therapeutic agents for the treatment or amelioration of IBDs, including UC and CD, and for the treatment of other TL1A-mediated diseases and conditions. The present invention meets these needs.

[0011] IL-12 and IL-23 are each involved in type 1 and type 3 (Th17) responses (77). IL-12 drives helper T1 (Th1) cell differentiation and interferon-γ (IFN-γ) production, while IL-23 promotes the maintenance of Th17 cells that produce IL-17 and other type 3 cytokines. Type 1 and type 3 responses are associated with various human inflammatory and autoimmune diseases. The important role of IL-12p40-containing cytokines has been established by numerous drug approvals (75) (IL-12p40 will hereafter be referred to simply as p40). The p40 neutralizing agent Stelara® (ustekinumab; Janssen) neutralizes IL-12 and IL-23 and is approved for the treatment of psoriasis vulgaris, psoriatic arthritis, Crohn's disease, and ulcerative colitis. The IL-23 selective anti-IL-23p19 blocking agents Tremfya® (guselkumab; Janssen), Skyrizi® (risankizumab; Boehringer Ingelheim / AbbVie), and Ilumya® (tildrakizumab; Sun Pharmaceutical) are approved for various psoriatic disorders.

[0012] Despite the effectiveness of current treatments, an unmet need remains for safe and effective therapeutics for numerous diseases characterized by an inflammatory response that address a broad range of disease mechanisms. SUMMARY OF THE INVENTION

[0013] For example, but not limited to, provided herein are antibodies (including antigen-binding fragments thereof) that specifically bind to TL1A, including bispecific TL1A-p40 antibodies, monovalent TL1A antibodies, other related antibodies, related nucleic acids, uses, and related methods. The present disclosure also provides methods for making, preparing, and producing the antibodies disclosed herein, including antibodies that bind to either or both of TL1A and p40. The antibodies of the present disclosure are useful in one or more of the diagnosis, prevention, or treatment of disorders or conditions mediated by or associated with one or more of TL1A and TL1A / p40 activities, including, but not limited to, the manufacture of medicaments for treating diseases, disorders, or conditions mediated by TL1A. In some embodiments, the disease, disorder, or condition is at least one selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis, and vasculitis.

[0014] The present disclosure further encompasses the expression of the antibodies, as well as the preparation and manufacture of compositions (e.g., medicaments using the antibodies) comprising the antibodies of the present disclosure.

[0015] Provided are not only polynucleotides encoding antibodies that specifically bind to TL1A, but also bispecific TL1A-p40 antibodies, monovalent TL1A antibodies, and other related antibodies. Also provided are polynucleotides encoding the heavy chain and / or light chain of the antibody. Host cells expressing the antibody are provided. Therapeutic methods of using the antibody are provided. Such methods include, but are not limited to, treating or preventing one or more diseases selected from the group consisting of TL1A, and diseases associated with or mediated by either or both of TL1A and p40 expression, or inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenosing Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis, and vasculitis.

[0016] The present invention can be more readily understood by reference to the following detailed description of the embodiments and examples of the invention included herein. It should be understood that the invention is not limited to the specific methods of manufacture that may be naturally subject to change. It should also be understood that the terminology used in this specification is for the purpose of describing specific embodiments only and is not intended to be limiting. One of ordinary skill in the art can recognize or confirm many equivalents to the specific embodiments of the invention described in the specification through routine experimentation. Such equivalents are intended to be encompassed by the following aspect (E).

[0017] E1. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and having the sequences of CDR-H1, CDR-H2, and CDR-H3 of TL1A-VH selected from the group consisting of the sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120; and the sequences of CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 18. E2. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and having the sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 42, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18. E3. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and having the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (iii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 32; (iv) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (v) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (vi) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (vii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (viii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 35; (ix) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (x) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xi) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xii) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xiii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 31; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xiv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 38; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xvi) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xvii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xviii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xix) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xx) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xxi) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; or, (xxii) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; An antibody containing a combination of heavy chain CDRs selected from the group consisting of: E4. An isolated antibody that specifically binds to TL1A, containing a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and containing the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, as well as the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32. E5. The antibody according to any one of E1 to E4, containing a framework sequence of TL1A-VH derived from a VH sequence of a human germline selected from the group consisting of IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, and IGHV1-2*02. E6. The antibody according to any one of E1 to E5, containing a framework sequence of TL1A-VH derived from the sequence of the human IGHV1-18*01 germline. E7. The antibody according to any one of E1 to E6, containing a framework sequence of TL1A-VL derived from a VL sequence of a human germline selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, and IGKV3-11*01. The antibody according to any one of E1 to E7, comprising a framework sequence of TL1A-VL derived from the IGKV1-39*01 sequence of the human germ cell lineage. E9. The antibody according to any one of E1 to E8, comprising a framework sequence of TL1A-VL and a framework sequence of TL1A-VH, wherein one or both of the framework sequence of TL1A-VL and the framework sequence of TL1A-VH are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of the human germ cell lineage from which it is derived. E10. The antibody according to any one of E1 to E9, comprising a framework sequence of TL1A-VL and a framework sequence of TL1A-VH, wherein one or both of the framework sequence of TL1A-VL or the framework sequence of TL1A-VH are identical to the sequence of the human germ cell lineage from which it is derived. E11. The antibody according to any one of E1 to E10, wherein the TL1A-VL contains the amino acid sequence shown in SEQ ID NO: 18, and the TL1A-VH contains a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120. E12. The antibody according to any one of E1 to E11, comprising a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 42, and a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 18. E13. The antibody according to any one of E1 to E12, comprising the TL1A-VH sequence shown in SEQ ID NO: 42 and the TL1A-VL sequence shown in SEQ ID NO: 18. The antibody according to any one of E1 to E13, comprising the sequence of TL1A-VH encoded by the nucleic acid sequence shown in SEQ ID NO: 228. The antibody according to any one of E1 to E14, comprising the sequence of TL1A-VL encoded by the nucleic acid sequence shown in SEQ ID NO: 229. The antibody according to any one of E1 to E15, comprising the sequence of TL1A-VH encoded by the plasmid deposited with ATCC under the accession number PTA-127347. The antibody according to any one of E1 to E16, comprising the sequence of TL1A-VL encoded by the plasmid deposited with ATCC under the accession number PTA-127348. The antibody comprising the sequence of TL1A-VH encoded by the plasmid deposited with ATCC under the accession number PTA-127347, and the sequence of TL1A-VL encoded by the plasmid deposited with ATCC under the accession number PTA-127438. E19. The IC of said TL1A 50 is less than 20 nM in a competitive ELISA, the antibody according to E1 to E18. E20. The IC of said TL1A 50 is less than 10 nM in a competitive ELISA, the antibody according to E1 to E19. E21. The IC of said TL1A 50 is less than 50 nM in a TF-1 NFκB reporter cell bioassay, the antibody according to E1 to E20. E22. The IC of said TL1A 50 is less than 30 nM in a TF-1 NFκB reporter cell bioassay, the antibody according to E1 to E21. E23. The IC of said TL1A 50 is less than 1 nM in a whole blood IFNγ assay, the antibody according to E1 to E22. E24. The IC of said TL1A 50 is less than 30 nM in a TF-1 NFκB reporter cell bioassay, the antibody according to E1 to E23. The antibody according to any one of E1 to E24, further comprising a heavy chain constant domain (TL1A-CH1) and a light chain constant domain (TL1A-CL). E26. The antibody according to E25, wherein the TL1A-CH1 contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. E27. The antibody according to E25 to E26, wherein the TL1A-CH1 contains the sequence shown in SEQ ID NO: 6. E28. The antibody according to E25 to E27, wherein the TL1A-CL contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16 and SEQ ID NO: 201. E29. The antibody according to E25 to E28, wherein the TL1A-CL contains the sequence shown in SEQ ID NO: 16. E30. The antibody according to E25 to E29, wherein the TL1A-CH1 is connected to the TL1A-VH, the TL1A-CL is connected to the TL1A-VL, and a TL1A-binding Fab domain (Fab of TL1A) is formed. E31. The antibody according to any one of E1 to E30, containing an antibody Fc domain containing a first Fc chain and a second Fc chain. E32. The Fc domain is IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM or IgG (e.g., IgG 1 , IgG 2 , IgG 3 or IgG 4 ), and the antibody according to E31. E33. The antibody according to E32, wherein the Fc domain is the Fc domain of IgG 1 . E34. The antibody according to E31 to E34, wherein the first Fc chain contains a first hinge region, a first CH2 region, and a first CH3 region from the N-terminus to the C-terminus, and the second Fc chain contains a second hinge region, a second CH2 region, and a second CH3 region from the N-terminus to the C-terminus. The antibody according to E33, comprising at least a first TL1A-CH1 domain, wherein the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain. The antibody according to any one of E35 to E37, wherein the first CH2 region and the second CH2 region each contain the sequence shown in SEQ ID NO: 8. The antibody according to E35, wherein either or both of the first hinge regions contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206. The antibody according to E44, wherein the hinge region contains the sequence shown in SEQ ID NO: 7. The antibody according to any one of E35 to E38, wherein the CH3 region of the first Fc chain and the CH3 region of the second Fc chain each contain the sequence shown in SEQ ID NO: 9. The antibody according to any one of E35 to E39, comprising a light chain (TL1A-LC) containing the sequence shown in SEQ ID NO: 19, and a heavy chain (TL1A-HC) containing a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 58, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 90, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 111, and SEQ ID NO: 121. The antibody according to any one of E35 to E40, comprising a light chain (TL1A-LC) containing the sequence shown in SEQ ID NO: 19 and a heavy chain (TL1A-HC) containing the sequence shown in SEQ ID NO: 43. The antibody according to any one of E34 to E41, comprising two identical Fab domains of TL1A. The antibody according to any one of E34 to E37, comprising a single Fab domain of TL1A. E44. The antibody according to E43, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain and the second Fc chain. E45. The first Fc chain contains a first CH3 region, the second Fc chain contains a second CH3 region, the first CH3 region and the second CH3 region each contain different complementary sequences, and the different complementary sequences are the following pair of complementary sequences: (i) SEQ ID NO: 160 and SEQ ID NO: 162; (ii) SEQ ID NO: 180 and SEQ ID NO: 183; (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and (iv) SEQ ID NO: 185 and SEQ ID NO: 187 The antibody according to E44, selected from the following: E46. The antibody according to E45, wherein the first CH3 region and the second CH3 region contain SEQ ID NO: 160 and SEQ ID NO: 162. E47. The antibody according to E44-E45, wherein the first hinge region and the second hinge region each contain one or more amino acid modifications that promote the association of the first hinge region and the second hinge region. E48. The first hinge region and the second hinge region each contain different complementary sequences, and the different complementary sequences are the following pair of complementary sequences: (i) SEQ ID NO: 179 and SEQ ID NO: 182; and (ii) SEQ ID NO: 189 and SEQ ID NO: 191 The antibody according to E47, selected from the following: E49. The antibody according to any one of E1-E48, characterized in that the score in an affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 4. E50. The antibody according to E43-E49, wherein the Fab domain of TL1A is fused to the first Fc chain and the second Fc chain is not fused to the Fab domain.

[0018] E51. An antibody containing a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 161, SEQ ID NO: 164, and SEQ ID NO: 165, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163, the antibody according to E43 to E50. E52. An antibody containing a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 161, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163, the antibody according to E43 to E51. E52. An antibody containing a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 164, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163, the antibody according to E43 to E51. E54. An antibody containing a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 165, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163, the antibody according to E43 to E51. E55. An antibody according to E43 - E49, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain (Fab of TL1A) that binds to TL1A, the second heavy chain and the second light chain contain a second Fab domain (Fab of xTL1A) that contains a non - binding TL1A - binding domain that does not specifically bind to a target, and the first light chain and the second light chain are identical. E56. The second Fab domain contains a non - binding TL1A heavy - chain variable region (xTL1A - VH) and a non - binding TL1A light - chain variable region (xTL1A - VL), and contains the sequence of CDR - L1 shown in SEQ ID NO: 11; the sequence of CDR - L2 shown in SEQ ID NO: 12; and the sequence of CDR - L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR - H1 shown in SEQ ID NO: 139; the sequence of CDR - H2 shown in SEQ ID NO: 140; the sequence of CDR - H3 shown in SEQ ID NO: 133; (ii) the sequence of CDR - H1 shown in SEQ ID NO: 128; the sequence of CDR - H2 shown in SEQ ID NO: 129; the sequence of CDR - H3 shown in SEQ ID NO: 130; (iii) the sequence of CDR - H1 shown in SEQ ID NO: 128; the sequence of CDR - H2 shown in SEQ ID NO: 129; the sequence of CDR - H3 shown in SEQ ID NO: 133; (iv) the sequence of CDR - H1 shown in SEQ ID NO: 128; the sequence of CDR - H2 shown in SEQ ID NO: 129; the sequence of CDR - H3 shown in SEQ ID NO: 136; (v) the sequence of CDR - H1 shown in SEQ ID NO: 139; the sequence of CDR - H2 shown in SEQ ID NO: 140; the sequence of CDR - H3 shown in SEQ ID NO: 130; (vi) the sequence of CDR - H1 shown in SEQ ID NO: 139; the sequence of CDR - H2 shown in SEQ ID NO: 140; the sequence of CDR - H3 shown in SEQ ID NO: 136; (vii) the sequence of CDR - H1 shown in SEQ ID NO: 147; the sequence of CDR - H2 shown in SEQ ID NO: 148; the sequence of CDR - H3 shown in SEQ ID NO: 130; (viii) the sequence of CDR - H1 shown in SEQ ID NO: 147; the sequence of CDR - H2 shown in SEQ ID NO: 148; the sequence of CDR - H3 shown in SEQ ID NO: 133; or, (ix) The sequence of CDR-H1 shown in SEQ ID NO: 147; the sequence of CDR-H2 shown in SEQ ID NO: 148; the sequence of CDR-H3 shown in SEQ ID NO: 136 The antibody according to E55, comprising . E57. The second Fab domain contains a heavy chain variable region (xTL1A-VH) and a light chain variable region (xTL1A-VL), and the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and the sequence of CDR-H1 shown in SEQ ID NO: 139; the sequence of CDR-H2 shown in SEQ ID NO: 140; the sequence of CDR-H3 shown in SEQ ID NO: 133. The antibody according to E55 to E56. E58. The second Fab domain contains the light chain variable amino acid sequence shown in SEQ ID NO: 18, and the second Fab domain contains a sequence selected from the group consisting of the heavy chain variable amino acid sequences shown in SEQ ID NO: 143, SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 149, SEQ ID NO: 151, and SEQ ID NO: 153. The antibody according to any one of E55 to E56. E59. The second Fab domain contains the light chain variable amino acid sequence shown in SEQ ID NO: 18, and the second Fab domain contains the heavy chain variable amino acid sequence shown in SEQ ID NO: 143. The antibody according to E58. E60. Comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain (Fab of TL1A) that binds to TL1A, and the second heavy chain and the second light chain contain a second Fab domain (Fab of xTL1A) that contains a non-binding TL1A binding domain that does not specifically bind to the target. The first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 161, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, the second antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 166. The antibody according to E55 to E59. E61. An antibody containing a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain (Fab of TL1A) that binds to TL1A, and the second heavy chain and the second light chain contain a second Fab domain (Fab of xTL1A) that contains a non-binding TL1A binding domain that does not specifically bind to a target, the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 161, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, the second antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 166, the antibody according to E55 to E60. E62. The antibody according to any one of E1 to E61, wherein the half-life of the antibody is less than 7 days in cynomolgus monkeys. E63. The antibody according to any one of E1 to E63, which is a high molecular weight species having a score of less than 2% as determined by analytical size exclusion chromatography (aSEC). E64. The antibody according to any one of E1 to E63, wherein the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 7. E65. The antibody according to any one of E1 to E64, wherein the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 6. E66. The antibody according to any one of E1 to E65, wherein the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 5. E67. The antibody according to any one of E1 to E66, wherein the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 4. E68. The antibody according to any one of E1 to E67, wherein the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 3. An antibody according to any one of E1 to E68, which is characterized in that in an E69. NFκB TL1A neutralization bioassay, the IC50 is less than 2 nM. E70. An antibody according to any one of E1 to E69, which is characterized in that when measured by SPR, the KD is less than 500 pM. E71. An antibody according to any one of E1 to E70, which is characterized in that when measured by SPR, the KD is less than 320 pM. E72. An antibody according to any one of E1 to E71, which is characterized in that when measured by SPR, the KD is less than 300 pM. E73. An antibody according to any one of E1 to E72, wherein the half-life of the antibody is at least 21 days in cynomolgus monkeys. E74. An antibody according to any one of E1 to E73, wherein the half-life of the antibody is at least 25 days in cynomolgus monkeys. E75. An antibody according to any one of E1 to E74, wherein the half-life of the antibody is at least 28 days in cynomolgus monkeys. E76. An antibody according to any one of E1 to E75, wherein the antibody binds to cynomolgus monkey TL1A with a size within one order of magnitude of human TL1A when measured by SPR. E77. An antibody according to any one of E1 to E76, wherein the antibody binds to human TL1A with an affinity at least 500-fold higher than that for mouse T1A when measured by SPR. E78. An antibody according to any one of E1 to E77, wherein the antibody binds to human TL1A with an affinity at least 2000-fold higher than that for mouse T1A when measured by SPR. E79. The antibody according to E1 to E38, which specifically binds to p40 via a p40 binding domain, contains a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), and contains the sequences of CDR-H1, CDR-H2 and CDR-H3 of the p40-VH sequence shown in SEQ ID NO: 171, and the sequences of CDR-L1, CDR-L2 and CDR-L3 of the p40-VL sequence shown in SEQ ID NO: 177. E80. The antibody specifically binds to p40 via a p40-binding domain, contains a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and has the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and the sequence of CDR-L3 shown in SEQ ID NO: 175, and the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; the sequence of CDR-H3 shown in SEQ ID NO: 169, and is the antibody according to E1 to E38. E81. An isolated antibody containing a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site contains a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), the second antigen-binding site contains a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), the p40-binding domain has the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and the sequence of CDR-L3 shown in SEQ ID NO: 175; and the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and the sequence of CDR-H3 shown in SEQ ID NO: 169, and the TL1A-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (iii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 32; (iv) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (v) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (vi) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (vii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (viii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 35; (ix) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (x) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xi) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xii) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xiii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 31; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xiv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 38; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xvi) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xvii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xviii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xix) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xx) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xxi) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; and, (xxii) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; An antibody further comprising a combination of heavy chain CDRs selected from the above. An isolated antibody comprising a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site comprises a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), the second antigen-binding site comprises a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and, (i) The p40-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and, the sequence of CDR-L3 shown in SEQ ID NO: 175; and, the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and, the sequence of CDR-H3 shown in SEQ ID NO: 169, and, (ii) The TL1A-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and, the sequence of CDR-L3 shown in SEQ ID NO: 13; and, the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; and, the sequence of CDR-H3 shown in SEQ ID NO: 32. Antibody. The antibody according to any one of E79 to E82, comprising a framework sequence of TL1A-VH derived from a VH sequence of a human germline selected from the group consisting of IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02. E84. The antibody according to any one of E79 to E83, comprising a framework sequence of TL1A-VH derived from the sequence of the human IGHV1-18*01 germline. E85. The antibody according to any one of E79 to E84, comprising a framework sequence of TL1A-VL derived from a VL sequence of a human germline selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01. E86. The antibody according to any one of E79 to E85, comprising a framework sequence of TL1A-VL derived from the sequence of the human germline IGKV1-39*01. E87. The antibody according to any one of E79 to E86, comprising a framework sequence of TL1A-VL and a framework sequence of TL1A-VH, wherein one or both of the framework sequence of TL1A-VL and the framework sequence of TL1A-VH are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of the human germline from which it is derived. E88. The antibody according to any one of E79 to E87, comprising a framework sequence of TL1A-VL and a framework sequence of TL1A-VH, wherein one or both of the framework sequence of TL1A-VL or the framework sequence of TL1A-VH are identical to the sequence of the human germline from which it is derived. E89. The TL1A-VL contains the amino acid sequence shown in SEQ ID NO: 18, and the TL1A-VH contains a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120. The antibody according to any one of E79 to E88. E90. The antibody according to any one of E79 to E89, which contains a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 42 and a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 18. E91. The antibody according to any one of E79 to E90, which contains the TL1A-VH sequence shown in SEQ ID NO: 42 and the TL1A-VL sequence shown in SEQ ID NO: 18. E92. The antibody according to any one of E79 to E91, which contains the TL1A-VH sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 228. E93. The antibody according to any one of E79 to E92, which contains the TL1A-VL sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 229. E94. The antibody according to any one of E1 to E15, which contains the TL1A-VH sequence encoded by the plasmid deposited with ATCC under the accession number PTA-127347. E95. The antibody according to any one of E1 to E16, which contains the TL1A-VL sequence encoded by the plasmid deposited with ATCC under the accession number PTA-127348. An antibody containing the sequence of TL1A-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127347, and the sequence of TL1A-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127438. E97. The antibody according to any one of E79 to E96, containing the framework sequence of p40-VH derived from the VH sequence of the human germ cell line selected from the group consisting of DP3, DP7, DP73, DP75 and DP88. E98. The antibody according to any one of E79 to E97, containing the framework sequence of p40-VH derived from the sequence of the human DP73 germ cell line. E99. The antibody according to any one of E79 to E98, containing the framework sequence of p40-VL derived from the VL sequence of the human germ cell line selected from the group consisting of DPK4, DPK5, DPK7, DPK8 and DPK9. E100. The antibody according to any one of E79 to E99, containing the framework sequence of p40-VL derived from the DPK9 sequence of the human germ cell line.

[0019] E101. The antibody according to any one of E79 to E100, containing the framework sequence of p40-VL and the framework sequence of p40-VH, wherein one or both of the framework sequence of p40-VL and the framework sequence of p40-VH are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of the human germ cell line from which it is derived. E102. The antibody according to any one of E79 to E101, containing the framework sequence of p40-VL and the framework sequence of p40-VH, wherein one or both of the framework sequence of p40-VL or the framework sequence of p40-VH are identical to the sequence of the human germ cell line from which it is derived. An antibody according to any one of E79 to E102, comprising a p40-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 177 and a p40-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 171. An antibody according to any one of E79 to E103, wherein the p40-VL contains the amino acid sequence shown in SEQ ID NO: 177 and the p40-VH contains the amino acid sequence shown in SEQ ID NO: 171. An antibody according to any one of E79 to E104, comprising a p40-VH sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 238. An antibody according to any one of E79 to E105, comprising a p40-VL sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 239. An antibody according to any one of E79 to E106, comprising a p40-VH sequence encoded by the plasmid deposited with ATCC under accession number PTA-127206. An antibody according to any one of E79 to E107, comprising a p40-VL sequence encoded by the plasmid deposited with ATCC under accession number PTA-127205. An antibody comprising a p40-VH sequence encoded by the plasmid deposited with ATCC under accession number PTA-127206 and a p40-VL sequence encoded by the plasmid deposited with ATCC under accession number PTA-127205. An antibody according to E79 to E109, wherein the TL1A-VH is fused to the CH1 domain (TL1A-CH1) and the TL1A-VL is fused to the light chain constant domain (TL1A-CL) to form a TL1A-binding Fab domain (Fab of TL1A). E111. The p40-VH is fused with the CH1 domain (p40-CH1), and the p40-VL is fused with the light chain constant domain (p40-CL), forming a p40-binding Fab domain (Fab of p40), the antibody according to E110. E112. The TL1A-CH1 contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199, the antibody according to E110 to E111. E113. The TL1A-CH1 contains the sequence shown in SEQ ID NO: 6, the antibody according to E100 to E102. E114. The TL1A-CL contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201, the antibody according to E100 to E113. E115. The TL1A-CL contains the sequence shown in SEQ ID NO: 16, the antibody according to E100 to E114. E116. The p40-CH1 contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199, the antibody according to E100 to E115. E117. The p40-CH1 contains the sequence shown in SEQ ID NO: 6, the antibody according to E100 to E116. E118. The p40-CL contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201, the antibody according to E100 to E117. E119. The p40-CL contains the sequence shown in SEQ ID NO: 16, the antibody according to E100 to E118. E120. The antibody contains an antibody Fc domain containing the first Fc chain and the second Fc chain, the antibody according to any one of E111 to E119. E121. The Fc domain is an Fc domain of IgA (for example, IgA 1 or IgA 2 ), IgD, IgE, IgM or IgG (for example, IgG 1 , IgG 2 , IgG 3 or IgG 4 ), the antibody according to E120. E122. The Fc domain is the Fc domain of IgG 1 The antibody according to E121, which is the Fc domain of 1 . E123. The first Fc chain contains, from the N-terminus to the C-terminus, a first hinge region, a first CH2 region, and a first CH3 region, and the second Fc chain contains, from the N-terminus to the C-terminus, a second hinge region, a second CH2 region, and a second CH3 region. The antibody according to E120 - E122 E124. The N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain. The antibody according to E123 E125. The N-terminus of the second Fc chain is connected to the C-terminus of the first p40-CH1 domain. The antibody according to E123 - E124 E126. The first CH2 region and the second CH2 region each contain the sequence shown in SEQ ID NO: 8. The antibody according to E123 - E125 E127. Either or both of the first hinge regions contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206. The antibody according to E123 - E126 E128. The first hinge region and the second hinge region each contain one or more amino acid modifications that promote the association of the first hinge region and the second hinge region. The antibody according to E123 - E127 E129. The first hinge region and the second hinge region each contain different complementary sequences, and the different complementary sequences are one of the following pairs of complementary sequences: (i) SEQ ID NO: 179 and SEQ ID NO: 182; (ii) SEQ ID NO: 189 and SEQ ID NO: 191 The antibody according to E128, which is selected from E130. The first hinge region contains the sequence shown in SEQ ID NO: 204. The antibody according to E123 - E128 E131. The second hinge region contains the sequence shown in SEQ ID NO: 7. The antibody according to E123 - E128 E132. The antibody according to E123 to E131, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain and the second Fc chain. E133. The first Fc chain contains a first CH3 region, the second Fc chain contains a second CH3 region, the first CH3 region and the second CH3 region each contain different complementary sequences, and the different complementary sequences are one of the following pairs of complementary sequences: (i) SEQ ID NO: 160 and SEQ ID NO: 162; (ii) SEQ ID NO: 180 and SEQ ID NO: 183; (iii) SEQ ID NO: 155 and SEQ ID NO: 158; (iv) SEQ ID NO: 185 and SEQ ID NO: 187 The antibody according to E123 to E132, selected from the above. E134. The antibody according to E123, wherein the first CH3 region and the second CH3 region contain SEQ ID NO: 160 and SEQ ID NO: 162. E135. The antibody according to any one of E79 to E134, wherein the antibody contains first, second, third, and fourth polypeptide chains, the first and third polypeptide chains together form the Fab of TL1A, and the second and fourth polypeptide chains together form the Fab of p40. E136. The first, second, third, and fourth polypeptide chains are (i) The sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (ii) The sequence of the first polypeptide is as shown in SEQ ID NO: 188, the sequence of the second polypeptide is as shown in SEQ ID NO: 186, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (iii) The sequence of the first polypeptide is as shown in SEQ ID NO: 192, the sequence of the second polypeptide is as shown in SEQ ID NO: 190, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (iv) The sequence of the first polypeptide is as shown in SEQ ID NO: 194, the sequence of the second polypeptide is as shown in SEQ ID NO: 193, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; and (v) The sequence of the first polypeptide is as shown in SEQ ID NO: 200, the sequence of the second polypeptide is as shown in SEQ ID NO: 196, the sequence of the third polypeptide is as shown in SEQ ID NO: 202, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 198; The antibody according to E135, having a combination of sequences according to any one of the groups selected from: E137. The antibody according to E135 - E136, wherein the sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178. E138. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody contains first, second, third, and fourth polypeptide chains, the first and third polypeptide chains together form the TL1A - binding region, the second and fourth polypeptide chains together form the p40 - binding region, and the sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody contains first, second, third, and fourth polypeptide chains, the first and third polypeptide chains together form the TL1A binding region, the second and fourth polypeptide chains together form the p40 binding region, and the first polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127349, the second polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127346, the third polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127350, and the fourth polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127203. E140. An isolated antibody that specifically binds to TL1A, the antibody containing CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. E141. An isolated antibody that specifically binds to TL1A, the antibody containing VH and VL of an antibody selected from one or more of Tables 30, 31, 32, and 33. E142. An isolated antibody that specifically binds to TL1A, the antibody being selected from one or more of Tables 30, 31, 32, and 33. E143. An isolated antibody that specifically binds to TL1A and p40, the antibody containing CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. E144. An isolated antibody that specifically binds to TL1A and p40, the antibody containing VH and VL of an antibody selected from one or more of Tables 30, 31, 32, and 33. E145. An isolated antibody that specifically binds to TL1A and p40, the antibody being selected from one or more of Tables 30, 31, 32, and 33. An antibody according to any one of E79 to E145, characterized in that the score in the affinity capture self-interacting nanoparticle spectroscopy (AC-SINS) assay is less than 2. E147. The antibody according to any one of E79 to E146, characterized in that at least 50% of the charge heterogeneity of the antibody is non-acidic and non-basic when measured by antibody imaging capillary electrophoresis (iCE) on a stress-free sample (T0) to be evaluated. E148. The antibody according to any one of E79 to E147, wherein the antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM when measured by SPR. E149. The antibody according to any one of E79 to E148, wherein the antibody binds to immobilized human TL1A with a binding affinity of less than 500 pM when measured by SPR. E150. The antibody according to any one of E79 to E149, wherein the antibody binds to immobilized human TL1A with a binding affinity of less than 300 pM when measured by SPR.

[0020] E151. The antibody according to any one of E79 to E150, wherein the immobilized antibody binds to human p40 with a binding affinity of less than 1 nM when measured by SPR. E152. The antibody according to any one of E79 to E151, wherein the immobilized antibody binds to human p40 with a binding affinity of less than 900 pM when measured by SPR. E153. The antibody according to any one of E79 to E152, wherein the immobilized antibody binds to human p40 with a binding affinity of less than 600 pM when measured by SPR. E154. The antibody according to any one of E79 to E153, wherein the antibody binds simultaneously to p40 (IL-23) and TL1A in an SPR assay, wherein the antibody is injected onto immobilized TL1A and the resulting complex is treated with IL-23. E155. The antibody according to E79 to E154, characterized in that in the human IL-12 neutralization Kit-225 assay, the IC 50 is less than 5 nM. E156. The antibody is characterized in that in the human IL-12 neutralization Kit-225 assay, IC 50 is less than 4 nM, and is the antibody according to E79 to E155. E157. The antibody is characterized in that in the human IL-12 neutralization Kit-225 assay, IC 50 is less than 2 pM, and is the antibody according to E79 to E156. E158. The antibody is characterized in that in the human IL-23 neutralization Kit-225 assay, IC 50 is less than 5 nM, and is the antibody according to E79 to E157. E159. The antibody is characterized in that in the human IL-23 neutralization Kit-225 assay, IC 50 is less than 4 nM, and is the antibody according to E79 to E158. E160. The antibody is characterized in that in the human IL-23 neutralization Kit-225 assay in human whole blood, IC 50 is less than 1 nM, and is the antibody according to E79 to E159. E161. The antibody is characterized in that in the human IL-23 neutralization Kit-225 assay in human whole blood, IC 50 is less than 0.5 nM, and is the antibody according to E79 to E160. E162. The Kit-225 assay is in human whole blood, and is the antibody according to E155 to E161. E163. The antibody is characterized in that in the cynomolgus monkey IL-23 neutralization Kit-225 assay, IC 50 is less than 5 nM, and is the antibody according to E79 to E162. E164. The antibody is characterized in that in the cynomolgus monkey IL-12 neutralization Kit-225 assay, IC 50 is less than 2 nM, and is the antibody according to E79 to E163. E165. The antibody is characterized in that in the cynomolgus monkey IL-12 neutralization Kit-225 assay, IC 50 is less than 1 nM, and is the antibody according to E79 to E164. E166. The antibody according to any one of E79 to E165, characterized in that in a human whole blood assay for measuring the inhibition of IFNγ, the IC 50 is less than 2 nM. E167. The antibody according to any one of E79 to E166, characterized in that in a human whole blood assay for measuring the inhibition of IFNγ, the IC 50 is less than 3 nM. E168. The antibody according to any one of E79 to E167, characterized in that in a human whole blood assay for measuring the inhibition of IFNγ, the IC 50 is less than 2 nM. E169. The antibody according to any one of E79 to E168, characterized in that in an isolated human CD4+ cell assay for measuring the inhibition of IFNγ, the IC 50 is less than 500 pM. E170. The antibody according to any one of E79 to E169, characterized in that in an isolated human CD4+ cell assay for measuring the inhibition of IFNγ, the IC 50 is less than 100 pM. E171. The antibody according to any one of E79 to E170, characterized in that in a human NFκB neutralization assay in TF-1 reporter cells, the IC 50 is less than 200 nM. E172. The antibody according to any one of E79 to E171, characterized in that in a human NFκB neutralization assay in TF-1 reporter cells, the IC 50 is less than 150 nM. E173. The antibody according to any one of E79 to E172, wherein the half-life of the antibody is at least 10 days in TG32 mice in a two-week analysis. E174. The antibody according to any one of E79 to E173, wherein the half-life of the antibody is at least 14 days in TG32 mice in a two-week analysis. E175. The antibody according to any one of E79 to E174, wherein the half-life of the antibody is at least 16 days in TG32 mice in a two-week analysis. E176. The antibody according to any one of E79 to E175, wherein the half-life of the antibody is at least 17 days in TG32 mice in a 2-week analysis. E177. The antibody according to any one of E79 to E176, wherein the half-life of the antibody is at least 21 days in cynomolgus monkeys. E178. The antibody according to any one of E79 to E177, wherein the half-life of the antibody is at least 25 days in cynomolgus monkeys. E179. The antibody according to any one of E79 to E178, wherein the half-life of the antibody is at least 28 days in cynomolgus monkeys. E180. The antibody according to any one of E1 to 179 for use as a medicament. E181. The use is for one or more treatments selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behçet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis, and vasculitis. The antibody according to E180. E182. The use is for inflammatory bowel disease (IBD). The antibody according to any one of E180 to E181. E183. The use is for Crohn's disease. The antibody according to any one of E180 to E182. E184. The use is for ulcerative colitis. The antibody according to any one of E180 to E183. A pharmaceutical composition comprising an antibody described in E1 to E184 in a therapeutically effective amount and a pharmaceutically acceptable carrier. E186. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody described in any one of E1 to E184 or the pharmaceutical composition described in E185. E187. The condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behçet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis, and vasculitis, the method according to E186. E188. The method according to any one of E186 to E87, comprising the step of administering the antibody or pharmaceutical composition subcutaneously. E189. The antibody or pharmaceutical composition is administered approximately twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months, the method according to any one of E186 to E188. E190. An isolated polynucleotide comprising one or more nucleotide sequences encoding an antibody described in any one of E1 to 184. E191. The polynucleotide according to E190, wherein the polynucleotide is RNA. E192. The polynucleotide according to E190 - E191, which contains at least one chemical modification. E193. The chemical modification is selected from pseudouridine, 1 - methylpseudouridine, N1 - methylpseudouridine, N1 - ethylpseudouridine, 2 - thiouridine, 4’ - thiouridine, 5 - methylcytosine, 2 - thio - 1 - methyl - 1 - deaza - pseudouridine, 2 - thio - 1 - methyl - pseudouridine, 2 - thio - 5 - azauridine, 2 - thio - dihydropseudouridine, 2 - thio - dihydrouridine, 2 - thio - pseudouridine, 4 - methoxy - 2 - thio - pseudouridine, 4 - methoxypseudouridine, 4 - thio - 1 - methyl - pseudouridine, 4 - thiopseudouridine, 5 - azauridine, dihydropseudouridine, 5 - methyluridine, 5 - methoxyuridine and 2'-O - methyluridine, and the polynucleotide according to E192. E194. The polynucleotide according to E190 - E191, which does not contain a chemical modification. E195. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to TL1A, wherein the nucleic acid contains the nucleic acid sequence shown in SEQ ID NO: 228, the nucleic acid sequence shown in SEQ ID NO: 229 or both. E196. An isolated polynucleotide encoding a polypeptide having VH of an antibody that binds to TL1A and a polypeptide having VL or both, wherein the nucleic acid contains the nucleic acid sequence shown in SEQ ID NO: 231, the nucleic acid sequence shown in SEQ ID NO: 233 or both. E197. An isolated polynucleotide encoding the VH, VL or both of an antibody that binds to TL1A, wherein the nucleic acid contains the nucleic acid sequence of the insert of the plasmid deposited with ATCC under accession number PTA - 127347, the nucleic acid sequence of the insert of the plasmid deposited with ATCC under accession number PTA - 127348 or both. An isolated polynucleotide encoding a polypeptide having a VH of an antibody that binds to TL1A and a polypeptide having a VL or both, wherein the nucleic acid contains the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127347, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127348, or both. E199. An isolated polynucleotide containing one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody contains a null-arm TL1A antibody containing a first variable heavy chain and a first variable light chain, and a second variable heavy chain and a second variable light chain, wherein the first variable heavy chain and the first variable light chain contain a first Fab domain that binds to TL1A (Fab of TL1A), and the second variable heavy chain and the second variable light chain contain a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to the target (Fab of xTL1A), and the first variable light chain and the second variable light chain are identical, and the polynucleotide contains the nucleic acid sequence shown in SEQ ID NO: 228, the nucleic acid sequence shown in SEQ ID NO: 230, and / or the nucleic acid sequence shown in SEQ ID NO: 260. E200. An isolated polynucleotide containing one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody contains a null-arm TL1A antibody containing a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain that binds to TL1A (Fab of TL1A), and the second heavy chain and the second light chain contain a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to the target (Fab of xTL1A), and the first light chain and the second light chain are identical, and the polynucleotide contains the nucleic acid sequence shown in SEQ ID NO: 231, the nucleic acid sequence shown in SEQ ID NO: 232, and / or the nucleic acid sequence shown in SEQ ID NO: 233.

[0021] An isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody comprises a null-arm TL1A antibody containing a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain that binds to TL1A (Fab of TL1A), and the second heavy chain and the second light chain contain a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to a target (Fab of xTL1A), wherein the first light chain and the second light chain are identical, and the polynucleotide contains one or more of the nucleic acid sequences of the insert of the plasmid deposited with the ATCC under accession number PTA-127347, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127348, and the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127351. E202. An isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) the sequence of TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 228, and the sequence of TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 229; and, (ii) the sequence of p40-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 238, and the sequence of p40-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 239; A polynucleotide containing. E203. An isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) the sequence of a polypeptide having TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 234, and the sequence of a polypeptide having TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 235; and, (ii) The sequence of p40-HC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 236, and the sequence of p40-LC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 237; A polynucleotide comprising E204. An isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) The sequence of TL1A-VH encoded by the plasmid deposited with ATCC under accession number PTA-127347, and the sequence of TL1A-VL encoded by the plasmid deposited with ATCC under accession number PTA-127348; and, (ii) The sequence of p40-VH encoded by the plasmid deposited with ATCC under accession number PTA-127206, and the sequence of p40-VL encoded by the plasmid deposited with ATCC under accession number PTA-127205 A polynucleotide comprising E205. An isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) A polypeptide sequence having TL1A-VH encoded by the plasmid deposited with ATCC under accession number PTA-127350, and a polypeptide sequence having TL1A-VL encoded by the plasmid deposited with ATCC under accession number PTA-127349; and, (ii) The sequence of p40-HC encoded by the plasmid deposited with ATCC under accession number PTA-127346, and the sequence of p40-LC encoded by the plasmid deposited with ATCC under accession number PTA-127203 A polynucleotide comprising E206. An isolated polynucleotide encoding the VH domain of a TL1A antibody, comprising the nucleic acid sequence shown in SEQ ID NO: 228. An isolated polynucleotide encoding the VL domain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 229. An isolated polynucleotide encoding the VH domain of a TL1A antibody engineered to eliminate TL1A binding, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 230. An isolated polynucleotide encoding the HC of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 231. An isolated polynucleotide encoding the HC of a TL1A antibody engineered to eliminate TL1A binding, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 232. An isolated polynucleotide encoding the LC of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 233. An isolated polynucleotide encoding the mFd chain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 234. An isolated polynucleotide encoding the LC-Fc chain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 235. An isolated polynucleotide encoding the HC of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 236. An isolated polynucleotide encoding the LC of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 237. An isolated polynucleotide encoding the VH of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 238. An isolated polynucleotide encoding the VL of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 239. A vector containing the polynucleotide according to E190 - E217. An isolated host cell containing the polynucleotide described in E219. E190 - E217 or the vector described in E218. E220. A method for producing an isolated antibody, the method comprising culturing the host cell described in E219 under conditions in which the antibody is produced and recovering the antibody. E221. A pharmaceutical composition containing a therapeutically effective amount of the antibody described in any one of E1 - E189 and a pharmaceutically acceptable carrier.

Brief Description of the Drawings

[0022]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0023] The headings used in this specification are for structural purposes only and should not be construed as limiting the subject matter described.

[0024] All references cited in this specification, including patent applications, patent publications, UniProtKB accession numbers, are incorporated herein by reference as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0025] The techniques and procedures described or referred to in this specification are generally well understood and are described, for example, in Sambrook et al, Molecular Cloning: A Laboratory Manual 3rd. edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel, et al. eds., (2003));the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R. I. Freshney, ed. (1987));Oligonucleotide Synthesis (M. J. Gait, ed., 1984);Methods in Molecular Biology, Humana Press;Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press;Animal Cell Culture (R. I. Freshney), ed., 1987);Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press;Cell and Tissue Culture Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons;Handbook of Experimental Immunology (D. M.It is generally used by those skilled in the art using conventional methods such as those widely used methods described in Weir and C. C. Blackwell, eds); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al, eds., 1994); Current Protocols in Immunology (J. E. Coligan et al, eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995) and their latest editions.

[0026] Definition Unless otherwise defined in the specification, scientific and technical terms used in connection with this invention have the meanings commonly understood by those skilled in the art.

[0027] As used herein, the singular form includes plural referents unless the context clearly dictates otherwise. For example, an antibody includes one or more antibodies.

[0028] When aspects or embodiments of the invention are described in terms of a Markush group of alternatives or other classification, the invention includes not only the entire recited group as a whole, but also each of the individual elements of the group, and all possible sub-groups of the main group, as well as the main groups in which one or more of the elements of the group are absent. The invention also contemplates an express exclusion of one or more of the elements of the claimed group of inventions.

[0029] The elements following the terms "for example" or "e.g." are not meant to be exhaustive or limiting.

[0030] As used herein, the term "about" when used to modify a parameter defined by a numerical value (e.g., *** such as a dosage) means that the parameter may vary by up to about 10% above or below the numerical value indicated for that parameter. For example, a dosage of about 5 mg means 5% ± 10%, i.e., it may vary from 4.5 mg to 5.5 mg.

[0031] Antibody "Antibody" refers to an immunoglobulin molecule that can specifically bind to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., located in the variable region of the immunoglobulin molecule via at least one antigen-binding site. As used herein, the term "antibody" can include any type of antibody (e.g., monospecific, bispecific), a portion of an intact antibody that retains the ability to bind to an antigen (e.g., "antigen-binding fragment"), and other modified arrangements of immunoglobulin molecules having an antigen-binding site.

[0032] The antibody includes antibodies of any class, such as IgG, IgA or IgM (or its subclass), and the antibody does not have to be of a specific class. Depending on the amino acid sequence of the antibody in the constant region of its heavy chain (HC), immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and some of these can be further divided into subclasses (isotypes), for example, IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2 may be further divided into. The heavy chain constant regions corresponding to different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional arrangements of different classes of immunoglobulins are well known.

[0033] Examples of antigen-binding fragments and modified arrangements of antibodies include: (i) Fab fragments (monovalent fragments consisting of VL, VH, CL and CH1 domains); (ii) F(ab’)2 fragments (bivalent fragments containing two Fab fragments linked by disulfide bridges in the hinge region); and (iii) Fv fragments consisting of the VL and VH domains of a single arm of an antibody. Furthermore, the two domains of VL and VH of the Fv fragment are encoded by separate genes, but they can be joined by a synthetic linker that enables them to be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (also known as single-chain Fv (scFv)); see, for example, Bird et al., Science 1988; 242:423-426 and Huston et al., Proc. Natl. Acad. Sci. USA, 1988, 85:5879-5883. Other forms of single-chain antibodies, such as diabodies, are also included.

[0034] In addition, antibodies lacking a C-terminal lysine (K) amino acid residue on the heavy chain polypeptide are further included (e.g., human IgG1 heavy chain contains a terminal lysine). As is known in the art, the C-terminal lysine may be clipped during antibody production, resulting in an antibody having a heavy chain lacking the C-terminal lysine. Alternatively, the antibody heavy chain may be produced using a nucleic acid that does not contain the C-terminal lysine.

[0035] Variable region The "variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, alone or in combination. As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions, which contribute to the formation of the antigen-binding site of the antibody. When variants of the variable region of interest having substitutions in amino acid residues outside the CDR regions (i.e., in the framework regions) are desired, appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the variable region of interest to the variable regions of other antibodies containing the same classical class CDR1 and CDR2 sequences as the variable region of interest (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).

[0036] In some embodiments, the final delineation of the CDRs and the identification of the residues having the binding site of the antibody are achieved by elucidating the structure of the antibody or the structure of the antibody-ligand complex. In some embodiments, this can be achieved by various techniques known to those of skill in the art, such as X-ray crystallographic analysis. In some embodiments, the CDR regions can be identified or inferred using various analytical methods. In some embodiments, the CDR regions can be identified or inferred using various analytical methods. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, the extended definition, and the conformation definition.

[0037] The Kabat definition is a standard for numbering residues in antibodies and is commonly used to identify CDR regions. See, for example, Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the position of certain structural loop regions. See, for example, Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The extended definition is a combination of the Kabat definition and the Chothia definition. The AbM definition uses integrated package software of a computer program created by Oxford Molecular Group for modeling antibody structures. See, for example, Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM (trademark), A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from its primary sequence using a combination of a knowledge database and the first method described in Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The contact definition is based on the analysis of the crystal structure of available complexes. See, for example, MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach in this specification, the “conformational definition” of CDR, the position of the CDR may be specified as residues that contribute an enthalpy to antigen binding.See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Further CDR boundary definitions may not strictly follow one of the above approaches, but nevertheless overlap at least in part with the Kabat CDRs and may be shortened or extended taking into account predictive or experimental findings that certain residues or groups of residues do not significantly affect antigen binding. As used herein, CDR may refer to CDRs defined by methods known in the art, including combinations of approaches. The methods used in this specification may utilize CDRs defined according to these approaches. For embodiments containing two or more CDRs, the CDRs may be defined according to one or more of the Kabat, Chothia, extended, AbM, contact or conformational definitions.

[0038] The Pfabat numbering method developed for consistent antibody numbering The Pfabat numbering method is a defined algorithm for consistent antibody numbering based on the Kabat numbering system (Sequences of Proteins of Immunological Interest, Fifth Edition by Kabat et al., NIH Publication NO: 91-3242, 1991). Unlike many other computer implementations of Kabat numbering, Pfabat numbers the entire human IgG1 heavy and light chains, including the constant (C) region and the heavy chain hinge. Figure 10 shows an example of numbering using underlined boldface complementarity determining region (CDR) residues. For the light chain, the CDR definitions are CDRL1 from residues L24-L34; CDRL2 from residues L50-L56; CDRL3 from residues L89-L97; CDRH1 from residues H26-H35 (including insertion positions such as H35B); CDRH2 from residues H50-H65; and CDRH3 from residues H95-H102. Note that the definition of CDRH1 used in the specification includes positions H26-H29, which is not included in some other interpretations of Kabat numbering.

[0039] Constant region The "constant region" of an antibody refers to either the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination. The IgG heavy chain constant region contains three contiguous immunoglobulin domains (CH1, CH2, and CH3) with a hinge region between the CH1 and CH2 domains. The IgG light chain constant region contains a single immunoglobulin domain (CL).

[0040] Fc domain and Fc chain "Fc domain" refers to a portion of an Ig molecule that correlates with the crystallizable fragment obtained by papain digestion of an immunoglobulin (Ig) molecule. As used herein, the term relates to the constant regions of the two chains of an antibody, where each chain excludes the first constant region immunoglobulin domain. Within the Fc domain, there are two "Fc chains" (e.g., "first Fc chain" and "second Fc chain"). An "Fc chain" generally refers to the C-terminal portion of an antibody heavy chain. Thus, an Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, as well as the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and the N-terminal flexible hinge relative to these domains.

[0041] The boundaries of the Fc chain may vary, but the Fc chain of a human IgG heavy chain is typically defined to include residues from C226 or P230 to its carboxyl terminus, where the numbering follows the EU index of Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1):78-85, as described in Kabat et al., 1991. An Fc chain typically includes amino acid residues approximately 236 to approximately 447 of the constant region of a human IgG1 heavy chain. "Fc chain" may refer to this polypeptide alone or in the context of a macromolecule (e.g., an antibody heavy chain or Fc fusion protein).

[0042] A "functional" Fc domain refers to an Fc domain having at least one effector function of a native sequence Fc domain. Representative "effector functions" include C1q binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation, among others. Such effector functions generally require the combination of an Fc domain with a binding domain (e.g., an antibody variable region), and can be evaluated using various assays known in the art for evaluating such antibody effector functions.

[0043] The Fc chain of a "native array" refers to an Fc chain containing an amino acid sequence identical to the amino acid sequence of the Fc chain found in nature. A "variant" Fc chain contains an amino acid sequence that differs from the Fc chain of the native array by at least one amino acid modification.

[0044] Monoclonal antibody A "monoclonal antibody" (mAb) refers to an antibody derived from a single copy or clone, including, for example, eukaryotic clones, prokaryotic clones, or phage clones. Monoclonal antibodies are highly specific and are made against a single antigenic site. Further, in contrast to polyclonal antibody preparations that include different antibodies made against different determinants (epitopes), each monoclonal antibody is typically made against a single determinant on the antigen. The modifier "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the production of antibodies by a particular method. For example, the monoclonal antibodies used in accordance with this invention may be produced by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or by recombinant DNA methods as described in U.S. Patent No. 4,816,567. In another example, monoclonal antibodies may be isolated from phage libraries such as those produced using the techniques described in McCafferty et al., 1990, Nature 348:552-554.

[0045] Human antibody "Human antibody" refers to an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human, or an amino acid sequence produced by a technique for manufacturing a fully human antibody. For example, a fully human antibody may be obtained by using a commercially available mouse engineered to express a specific human immunoglobulin protein, or by a library (e.g., phage, yeast or ribosome) display technique for manufacturing a fully human antibody. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues.

[0046] Chimeric antibody "Chimeric antibody" refers to an antibody in which the sequence of the variable region is derived from one species and the sequence of the constant region is derived from another species, such as an antibody in which the sequence of the variable region is derived from a mouse antibody and the sequence of the constant region is derived from a human antibody.

[0047] Humanized antibody "Humanized" antibody refers to a non-human (e.g., mouse) antibody that is a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the CDRs of the recipient have been replaced by residues derived from the CDRs of a non-human species (donor antibody), such as a mouse, rat or rabbit, that have the desired specificity, affinity and capacity. A humanized antibody is not found in the recipient antibody or in the incorporated CDR or framework sequences, but may have residues included to further improve and optimize the performance of the antibody.

[0048] Antigen "Antigen" refers to a molecular entity used for immunizing an immunocompetent vertebrate for screening an expression library (e.g., phage, yeast or ribosome display library, etc.) for producing an antibody that recognizes the antigen or for antibody selection. In this specification, an antigen is more broadly referred to and generally includes a target molecule specifically recognized by an antibody, and thus is intended to include fragments or mimetics of molecules used in an immunization method for generating an antibody or in library screening for antibody selection.

[0049] Epitope "Epitope" refers to an area or region of an antigen to which an antibody specifically binds, determined by methods well known in the art, e.g., an area or region containing residues that interact with the antibody. For example, methods for mapping and characterizing the position of epitopes on a protein, including elucidation of the crystal structure of an antibody-antigen complex, competitive assays, gene fragment expression assays, epitope mapping and synthetic peptide-based assays, as described in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999, are well known in the art. Additionally, alternatively, during discovery, the production and characterization of an antibody may provide information about the desired epitope. From this information, it becomes possible to competitively screen for antibodies that bind to the same epitope.

[0050] Binding affinity The term "binding affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, in this specification, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between the elements of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y is generally the dissociation constant (K D) can be represented by. Affinity can be measured by common methods known in the art. Low-affinity antibodies generally bind to antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind to antigens faster and tend to remain bound longer. In particular, the term "binding affinity" is intended to refer to the dissociation rate of a particular antigen-antibody interaction. K D is the "off rate (k off )" or the association rate of the dissociation rate also called "k d " or the "on rate (k on )" or the ratio to "k a ". Therefore, K D is equal to k off / k on (or k d / k a ) and is expressed as molar concentration (M). It can be seen that as K D becomes smaller, the binding affinity becomes stronger. Therefore, a K D of 1 μM shows a weaker binding affinity compared to a K D of 1 nM. The K D value for an antibody can be determined by methods well established in the art. A typical method for determining the K D of an antibody is to use surface plasmon resonance (SPR), typically by using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of an antigen from a chip having immobilized molecules (e.g., molecules containing an epitope-binding domain) on their surface. Another method for determining the K D of an antibody is to use biolayer interferometry, typically by using an OCTET® technology (Octet QK e system, ForteBio). Alternatively or in addition, a KinExA (binding equilibrium exclusion method) assay available from Sapidyne Instruments (Boise, ID) can also be used.

[0051] Monospecific antibody "Monospecific antibody" refers to an antibody having one or more antigen-binding sites per molecule, such that all binding sites of the antibody specifically recognize the same epitope on an antigen. Thus, where a monospecific antibody has more than two antigen-binding sites, the binding sites compete with each other for binding to a single antigen molecule.

[0052] Bispecific antibody "Bispecific antibody" refers to a molecule having binding specificities for at least two different epitopes. In some embodiments, a bispecific antibody can bind to two different antigens simultaneously. In other embodiments, the two different epitopes may be present on the same antigen.

[0053] One-arm antibody A one-arm antibody is an IgG antibody containing an intact Fc domain of two hinge domains, two CH2 domains and two CH3 domains, and only one Fab region. A one-arm antibody is monovalent and monospecific because it has only a single Fab domain. Figure 1 depicts a schematic of a one-arm antibody.

[0054] Null-arm antibody or inactivated antibody An antibody containing a null arm (also denoted "inactivated") is a monovalent monospecific antibody, wherein one of the antigen-binding sites is modified (synonymous with engineered) to preclude binding to the target. One or more of the heavy chain CDRs may be modified to preclude binding to the target, and advantageously, the light chain CDRs may not be modified to facilitate antibody production and minimize mispairing. The modification or engineering may be shown by a documented method in which at least one structural feature is retained in the process steps of each method. Figure 1 depicts a schematic of a null-arm antibody.

[0055] Half maximal effective concentration (EC 50 ) "Half maximal effective concentration (EC 50The term "]]" refers to the concentration of a therapeutic agent that causes a response halfway between the baseline and the maximum after a specified exposure time. The therapeutic agent may cause inhibition or stimulation. EC 50 values are commonly used as a measure of potency and are also used in this specification.

[0056] Agonist An "agonist" refers to a substance that promotes (i.e., induces, causes, enhances, or increases) the biological activity or effect of another molecule. The term agonist includes substances (such as antibodies) that bind to a molecule and promote its activity.

[0057] Antagonist An "antagonist" refers to a substance that prevents, blocks, inhibits, neutralizes, or reduces the biological activity or effect of another molecule, such as a receptor. The term antagonist includes substances (such as antibodies) that bind to a molecule and prevent or reduce its activity.

[0058] Compete As used herein with respect to antibodies, the term "competing" means that the binding of a second antibody to its cognate epitope is detectably decreased in the presence of a first antibody as compared to the binding of the second antibody in the absence of the first antibody, in a manner sufficiently similar to the binding of the second antibody such that the first antibody binds to the epitope. There may or may not be an option that the binding of the first antibody to its epitope is also detectably decreased in the presence of the second antibody. That is, the first antibody can inhibit the binding of the second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its individual epitope. However, if each antibody detectably inhibits the binding of the other antibody to its cognate epitope or ligand, the antibodies are said to "cross-compete" with each other with respect to the binding of their individual epitopes, whether to the same, higher or lower degree. Both competing antibodies and cross-competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or a portion thereof), one of ordinary skill in the art will recognize, based on the teachings provided herein, that such competing or cross-competing antibodies are encompassed by and can be useful for the methods disclosed herein.

[0059] Host cell "Host cell" refers to an individual cell or cell culture that can or has been a recipient for a vector containing a polynucleotide insert. Host cells include the progeny of a single host cell, which progeny may not necessarily be identical, due to natural, accidental or deliberate mutations, to the original parent cell (either in morphology or in genomic DNA complement). Host cells include cells transfected in vivo with the polynucleotides of the present invention.

[0060] Vector "Vector" refers to a construct that can deliver, preferably express, one or more genes or sequences of interest (e.g., antibody-encoding genes) in a host cell. Examples of vectors include, but are not limited to, plasmids and viral vectors, and may include naked nucleic acids or nucleic acids associated with delivery assistance materials (e.g., cationic condensing agents, liposomes, etc.). The vector may contain DNA or RNA. "Expression vector" refers herein to a vector containing at least one polypeptide-encoding gene and at least one regulatory element (e.g., promoter sequence, poly(A) sequence) associated with the transcription or translation of the gene. Vectors used in this specification usually contain at least one antibody-encoding gene and one or more of regulatory elements or selectable markers. The components of the vector may include, for example, the following: signal sequence; origin of replication; one or more marker genes; one or more suitable transcriptional control elements (such as promoters, enhancers, and terminators). For translation, one or more translational control elements such as ribosome binding sites, translation initiation sites, and stop codons may also be included.

[0061] Isolated An "isolated" molecule (e.g., antibody) is one that is (1) not associated with the naturally associated components with which it is associated in its native state, by virtue of its origin or source, (2) substantially free of other molecules from the same origin (e.g., species, the cell in which it is expressed, library, etc.), (3) expressed by cells of a different species, or (4) not naturally occurring. Thus, a chemically synthesized molecule or a molecule expressed in a cell line different from its natural origin system is "isolated" from its naturally associated components. Molecules may also be made substantially free of naturally associated components by isolation using purification techniques well known in the art.

[0062] Polypeptide / Protein "Polypeptide" or "protein" (used interchangeably in this specification) refers to a chain of amino acids of any length. The chain may be linear or branched. The chain may contain one or more modified amino acids. The term encompasses natural amino acid chains, or amino acid chains modified by other manipulations or modifications such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with a labeling component. For example, polypeptides containing one or more amino acid analogs (including, for example, non-natural amino acids) and other modifications known in the art are also included within this definition. It is understood that a polypeptide can exist as a single chain or as associated chains.

[0063] Polynucleotide / Nucleic acid "Polynucleotide" or "nucleic acid" (used interchangeably herein) refers to a chain of nucleotides of any length, including DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases or their analogs, or substances capable of being incorporated into the chain by DNA or RNA polymerase. Polynucleotides may contain modified nucleotides such as methylated nucleotides and their analogs. When present, modifications to the nucleotide structure may be imparted before or after assembly of the chain. The nucleotide sequence may be interrupted by elements that are not nucleotides. Polynucleotides may be further modified after polymerization, such as by attachment to a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with analogs, internucleotide modifications such as those having uncharged linkages (e.g., methylphosphonate, phosphotriester, phosphoramidate, carbamate, etc.) and charged linkages (e.g., phosphorothioate, phosphorodithioate, etc.), polynucleotides containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those having intercalators (e.g., acridine, psoralen, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, oxidizing metals, etc.), those containing alkylating agents, those having modified linkages (e.g., α-anomer nucleic acids, etc.), as well as the unmodified forms of the polynucleotides. Further, the hydroxyl groups normally present on the sugar may be substituted, for example, with phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to further bind to additional nucleotides, or conjugated to a solid support. The 5' and 3' terminal OHs can be phosphorylated or substituted with an amine or an organic capping group moiety of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized with standard protecting groups.The polynucleotide can also contain analog forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α or β-anomeric sugars, epimeric sugars such as arabinose, xylose or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs and abasic nucleoside analogs such as methyl riboside.

[0064] Conservative substitution "Conservative substitution" refers to the substitution of a residue of an amino acid with a biologically, chemically or structurally similar residue. Biologically similar means that the substitution does not destroy biological activity. Structurally similar means that the amino acid has a side chain of similar length or similar size, such as alanine, glycine and serine. Chemical similarity means that the residues have the same charge, or are both hydrophilic or hydrophobic. Specific examples include substitution of a hydrophobic residue such as isoleucine, valine, leucine or methionine with another one, or substitution of arginine with lysine, substitution of glutamic acid with aspartic acid or substitution of glutamine with asparagine, substitution of one polar residue with another such as substitution of serine with threonine. Specific examples of conservative substitutions include substitution of a hydrophobic residue such as isoleucine, valine, leucine or methionine with another one, or substitution of a polar residue such as substitution of arginine with lysine, substitution of glutamic acid with aspartic acid or substitution of glutamine with asparagine. Conservative amino acid substitutions typically include, for example, substitutions within glycine, alanine, valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.

[0065] Identity The term "identity" or "identical to..." refers to the overall relatedness between polymer molecules, for example, between nucleic acid molecules (e.g., DNA molecules or RNA molecules) or between polypeptide molecules. "Identity" measures the percentage of identity between two or more sequences using gap alignment addressed by a computer program (e.g., an algorithm) of a specific mathematical model well-known in the art.

[0066] The terms "increase", "improve", "decrease", or "reduce" refer to a value compared to a baseline measurement such as a measurement in the same individual before the start of the treatment described in the specification or a measurement in a control individual or subject (or multiple control individuals or subjects) in the absence of the treatment described in the specification. In some embodiments, the "control individual" is an individual suffering from the same form of disease or injury as the individual being treated. In some embodiments, the "control individual" is an individual not suffering from the same form of disease or injury as the individual being treated.

[0067] Excipient The term "excipient" refers to a material that is combined with the active ingredient of interest (e.g., an antibody) and enables the active ingredient to retain its biological activity. The choice of excipient depends largely on factors such as the method of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "excipient" includes any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, carrier, diluent, etc. Examples of excipients include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., and one or more combinations thereof, and isotonic agents such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol may be included in the composition.

[0068] Treat The term "treating" or "treatment" refers to a treatment that, for example, alleviates, reduces or delays the progression of a patient's disease, disorder or condition, or tissue damage associated with the disease. In some embodiments, the disease, disorder or condition is inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behçet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, urological and defecation disorders, uveitis and vasculitis, and is one or more selected from the group consisting of.

[0069] Prevent The term "preventing" or "prevention" refers to one or more of the delay in the onset of at least one sign or symptom of a particular disease, disorder or condition (e.g., *** ), the reduction in its frequency or the reduction in its severity (e.g., specific to a particular application *** ). In some embodiments, prevention is evaluated on a population basis, such that if a statistically significant decrease in the occurrence, frequency or intensity of one or more symptoms of a disease, disorder or condition is observed in a population susceptible to the disease, disorder or condition, the agent is considered to "prevent" a particular disease, disorder or condition. Prevention may be considered complete if the onset of the disease, disorder or condition is delayed over a predetermined period.

[0070] Subject The terms "subject", "individual" or "patient" (used interchangeably herein) refer to any animal, including mammals. Mammals according to the invention include dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans, etc., and also include mammals in utero. In one aspect, humans are preferred subjects. Human subjects may be of any gender and at any stage of development. In some aspects, the subject is a patient having one or more diseases or disorders selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenosing Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis and vasculitis.

[0071] Therapeutically effective amount The term "therapeutically effective amount" refers to the amount of an active ingredient that elicits a biological or medical response in a tissue, system, animal, individual or human as determined by a researcher, veterinarian, physician or other clinician, and may include one or more of the following: (1) Preventing a disease; for example, preventing a disease, condition or disorder in an individual who may be a factor for a disease, condition or disorder but has not yet experienced or presented the symptoms or manifestations of the disease; (2) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual experiencing or presenting the pathology or symptoms of the disease, condition or disorder (i.e., stopping or delaying the further occurrence of the pathology or symptoms); and, (3) ameliorating a disease; for example, ameliorating a disease, condition or disorder in an individual experiencing or presenting the pathology or symptoms of the disease, condition or disorder (i.e., reversing the pathology or symptoms).

[0072] Antibody against TL1A The present disclosure provides an antibody that binds to tumor necrosis factor-like ligand 1A (TL1A). TL1A is also known as vascular endothelial growth inhibitor (VEGI) and TNF superfamily member 15 (TNFSF15).

[0073] As used herein, the term "TL1A" includes variants, isoforms, homologs, orthologs and paralogs of TL1A. In some embodiments, the antibodies disclosed herein cross-react with TL1A from non-human species such as cynomolgus monkey TL1A and different forms of TL1A. In some embodiments, the antibody may be completely specific for human TL1A and may not exhibit species cross-reactivity (e.g., does not bind to mouse TL1A) or other types of cross-reactivity. As used herein, the term "TL1A" refers to naturally occurring human TL1A unless the context indicates otherwise. Thus, "TL1A antibody", "anti-TL1A antibody" or other similar designations mean an antibody (as defined herein) that binds or reacts with TL1A, its isoforms, fragments or derivatives. The full-length mature form of TL1A represented by UniProtKB / Swiss-Prot accession number AAI04463.1 is provided herein as SEQ ID NO: 208. The full-length mature form of mouse TL1A represented by UniProtKB / Swiss-Prot accession number Q5UBV8 is provided herein as SEQ ID NO: 211. The full-length mature form of cynomolgus monkey TL1A represented by UniProtKB / Swiss-Prot accession number XP_005581018.1 is provided herein as SEQ ID NO: 209.

[0074] TL1A, a member of the TNF superfamily, is a homotrimeric cytokine expressed by innate immune cells including monocytes, macrophages and dendritic cells upon induction by cross-linking of Fc receptors by ICs or stimulation of TLRs. A small subset of activated T cells, endothelial cells and fibroblasts also express TL1A 20、21、22。TL1A engages its receptor DR3, which is expressed under inflammatory conditions in lymphocytes, NK cells, NKT cells, ILCs, and epithelial cells, to enhance the production of pro-inflammatory and profibrotic cytokines and can also bind to the decoy receptor DcR3, which functions as a negative regulator. TL1A can enhance the activity of Th1 and Th17 cells by synergizing with IL-12 and IL-23 to increase cell proliferation and cytokine secretion. Importantly, TL1A can promote cytokine production in memory T cells in the presence of IL-15 and IL-18 independently of IL-12 and IL-23. In addition to the direct activation of immune cells, recent studies have shown the promotion of intestinal fibrosis by the aversion of myofibroblast activity 30 , as well as an additional role for TL1A in the induction of an epithelial damage response, including IL-8 secretion and reduced barrier function due to a negative effect on tight junction proteins. A series of multiple lines of evidence, including a number of genome-wide association studies indicating several genetic polymorphisms in the TL1A gene (TNFSF15), which has been identified as an IBD susceptibility locus in patient populations in Europe and Asia, suggest a prominent role for TL1A in IBD. 30、33 。In addition, increased expression of TL1A has been reported in inflamed tissues of IBD patients. 21、34 。

[0075] Without wishing to be bound by a particular theory, blockade of TL1A cell ligand interactions inhibits the direct activation of immune cells and intestinal fibrosis.

[0076] A neutralizing antibody or “blocking” antibody refers to an antibody whose binding to TL1A either (i) prevents, limits, or inhibits the interaction between TL1A and its ligands, such as the DR3 receptor; or (ii) results in the inhibition of at least one biological function of ligand binding. Assays for determining neutralization by the antibodies of the present disclosure are well known in the art.

[0077] The biological function or biological activity of TL1A can, although not necessarily, be mediated by the interaction between TL1A and its ligand.

[0078] The anti-TL1A antibodies of the present disclosure include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab’, F(ab’) 2 , Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single-chain (ScFv), variants thereof, fusion proteins containing antibody fragments (e.g., domain antibodies), humanized antibodies, as well as glycosylation variants of antibodies, amino acid sequence variants of antibodies, and antibodies modified by covalent bonds, and other modified arrangements of immunoglobulin molecules having an antigen-binding site with the required specificity can be included. The antibodies may be of mouse, rat, human, or other origin (including chimeric antibodies or humanized antibodies). In some embodiments, the anti-TL1A antibody is a monoclonal antibody. In some embodiments, the anti-TL1A antibody is a human antibody or a humanized antibody. In some embodiments, the anti-TL1A antibody is a chimeric antibody.

[0079] In some embodiments, the present invention provides a TL1A antibody having a light chain variable region (VL) sequence and a heavy chain variable region (VH) sequence or a variant thereof found in one or more of Table 30, Table 31, Table 32, and Table 33.

[0080] The present invention also provides the CDR portions of the antibodies against TL1A. The determination of the CDR regions is defined in Example 1. In some embodiments, the antibody contains any one of the three CDRs of any one of the heavy chain variable regions shown in one or more of Table 30, Table 31, Table 32, and Table 33. In some embodiments, the antibody contains any one of the three CDRs of any one of the light chain variable regions shown in one or more of Table 30, Table 31, Table 32, and Table 33. In some embodiments, the antibody contains any one of the three CDRs of any one of the heavy chain variable regions and any one of the three CDRs of any one of the light chain variable regions respectively shown in one or more of Table 30, Table 31, Table 32, and Table 33.

[0081] In some embodiments, the antibody contains the six CDRs of a TL1A antibody selected from one or more of Tables 30, 31, 32, and 33. In some embodiments, the antibody contains the VH and VL of a TL1A antibody each selected from one or more of Tables 83, 84, 85, 86, and 87. In some embodiments, the antibody contains the HC and LC of a TL1A antibody each selected from one or more of Tables 30, 31, 32, and 33.

[0082] In some embodiments, the present disclosure provides anti-TL1A antibodies containing variant forms of the CDR, VH, VL, HC, and LC regions shown in one or more of Tables 30, 31, 32, and 33, wherein such variant polypeptides have at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the amino acid sequences disclosed in one or more of Tables 30, 31, 32, and 33. These amounts are not intended to be limiting, and increases in the recited percentages are specifically contemplated as part of this disclosure.

[0083] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A and contains a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), (i) the sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 42, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (ii) the sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 44, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (iii) the sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 47, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (iv) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 49, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (v) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 52, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (vi) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 54, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (vii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 57, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (viii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 70, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (ix) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 72, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (x) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 78, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xi) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 80, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 89, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xiii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 93, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xiv) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 95, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xv) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 97, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xvi) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 99, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xvii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 101, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xviii) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 103, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xix) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 105, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; (xx) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 110, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18; and (xxi) The sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 120, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18 An antibody is provided that contains a sequence selected from the group consisting of.

[0084] In some aspects, the disclosure provides an isolated antibody that specifically binds to TL1A and contains a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and contains the sequences of CDR-H1, CDR-H2, and CDR-H3 shown in SEQ ID NO: 42, and the sequences of CDR-L1, CDR-L2, and CDR-L3 shown in SEQ ID NO: 18.

[0085] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A and contains a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), and contains the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (iii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 32; (iv) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (v) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (vi) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (vii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (viii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 35; (ix) the sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (x) the sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xi) the sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xii) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xiii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 31; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xiv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 38; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xvi) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xvii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xviii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xix) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xx) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xxi) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; or, (xxii) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; To provide an antibody containing a combination of heavy chain CDRs selected from the following.

[0086] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A and contains a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, as well as the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; and the sequence of CDR-H3 shown in SEQ ID NO: 32.

[0087] The TL1A antibody may contain a framework sequence of TL1A-VH that contains a framework sequence of VH of the human germline. The framework sequence of TL1A-VH may contain one or more amino acid substitutions, additions, or deletions while still retaining functional and structural similarity to the germline from which it is derived. In some aspects, the framework of VH is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the framework sequence of VH of the human germline. In some aspects, the TL1A antibody contains a framework sequence of TL1A-VH that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions relative to the framework sequence of VH of the human germline. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions are only in the framework region. In some aspects, the % identity is based on similarity to VH excluding the portions defined as CDRs in this specification.

[0088] In some aspects, the framework sequence of TL1A-VH may be derived from the sequence of VH of a human germline selected from the group consisting of IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02 and IGHV1-2*02. The foregoing framework is modeled to be compatible with the TL1A-VH CDR of the present invention. The present invention has identified the human germline VH framework IGHV1-18*01 as being very advantageous with the TL1A-VLH CDR of the present invention. In some aspects, the framework sequence of TL1A-VH is derived from IGHV1-18*01.

[0089] The TL1A antibody may contain a framework sequence of TL1A-VL that contains a framework sequence of VL of a human germline. The framework sequence of TL1A-VL may contain one or more amino acid substitutions, additions or deletions while still retaining the functional and structural similarity to the germline from which it is derived. In some aspects, the framework of VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the framework sequence of VL of a human germline. In some aspects, the TL1A antibody contains a framework sequence of TL1A-VL that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the framework sequence of VL of a human germline. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on the similarity to VL excluding the portion defined as CDR in this specification.

[0090] The framework sequence of TL1A-VL may be derived from the sequence of VH of a human germline selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, and IGKV3-11*01. The aforementioned framework is modeled to be compatible with the TL1A-VL CDR of the present invention. The present invention has identified the human germline VL framework IGKV1-39*01 as being very advantageous with the TL1A-VL CDR of the present invention. In some aspects, the framework sequence of TL1A-VH is derived from IGKV1-39*01.

[0091] TL1A-VL may contain the amino acid sequence shown in SEQ ID NO: 18, and TL1A-VH may contain a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120.

[0092] The TL1A antibody may contain a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 42, and may contain a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 18. The TL1A antibody may contain the TL1A-VH sequence shown in SEQ ID NO: 42 and the TL1A-VL sequence shown in SEQ ID NO: 18.

[0093] The TL1A antibody may further contain a heavy chain constant domain (TL1A-CH1) and a light chain constant domain (TL1A-CL). In some aspects of the present disclosure, the TL1A-CH1 of the antibody contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. In some aspects of the present disclosure, the TL1A-CL of the antibody contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16 and SEQ ID NO: 201. TL1A-CH1 may contain the sequence shown in SEQ ID NO: 6. TL1A-CL may contain the sequence shown in SEQ ID NO: 16. TL1A-CH1 and TL1A-CL may each be part of a multispecific antibody.

[0094] TL1A-CH1 may be connected to TL1A-VH, and TL1A-CL may be connected to TL1A-VL, forming a TL1A-binding Fab domain (Fab of TL1A).

[0095] In some aspects, the antibody contains a Fab domain of a single TL1A. Examples of antibodies with a Fab domain of a single TL1A are one-armed antibodies and bispecific antibodies.

[0096] The TL1A antibody of the present invention may contain an antibody Fc domain containing a first Fc chain and a second Fc chain. The Fc domain may be an Fc domain of IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM, or IgG (e.g., IgG 1 , IgG 2 , IgG 3 or IgG 4 ). The Fc domain is IgG 1It may also be the Fc domain. The first Fc chain may contain, from the N-terminus to the C-terminus, a first hinge region, a first CH2 region, and a first CH3 region, and the second Fc chain may contain, from the N-terminus to the C-terminus, a second hinge region, a second CH2 region, and a second CH3 region. In some aspects, the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain and the second Fc chain.

[0097] The antibody of the present invention may contain a hinge region. The hinge region may be selected from any suitable sequence, including a sequence selected from Table 30, Table 31, Table 32, and Table 33. In some aspects, the hinge region is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, and SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206.

[0098] In some aspects, the first hinge region and the second hinge region each contain one or more amino acid modifications that promote the association of the first hinge region and the second hinge region. The first hinge region and the second hinge region may each contain different complementary sequences, and the different complementary sequences are one of the following pairs of complementary sequences: (i) SEQ ID NO: 179 and SEQ ID NO: 182; and, (ii) SEQ ID NO: 189 and SEQ ID NO: 191 and may be selected from.

[0099] In some aspects particularly suitable for one-armed antibody variants, the antibody may contain a modified full-length hinge for a cleaved Fc containing the C(H230)S mutation (SEQ ID NO: 157). SEQ ID NO: 179 is a full-length hinge suitable for the charge variant RRR / EEE with D(H232)R and P(H241)R mutations. SEQ ID NO: 182 is a full-length hinge suitable for the charge variant RRR / EEE with D(H232)E and P(H241)E mutations. Thus, SEQ ID NO: 179 and SEQ ID NO: 182 are pairs of different complementary hinge sequences. SEQ ID NO: 189 is a full-length hinge suitable for the charge variant RR / EE with D(H232)R mutation. SEQ ID NO: 191 is a full-length hinge suitable for the charge variant RR / EE with D(H232)E mutation. Thus, SEQ ID NO: 189 and SEQ ID NO: 191 are pairs of different complementary hinge sequences. SEQ ID NO: 204 is a lower hinge region starting at D(H232) and extending to and including P(H243). SEQ ID NO: 206 is an upper hinge region starting at E(H226) and extending to and including C(H230) (note that SEQ ID NO: 204 and 206 are not complete hinge regions but are part of the mFd KiH bispecific antibody format).

[0100] The TL1A antibody of the present invention may optionally contain at least a first TL1A-CH1 domain, and the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain. TL1A-CL may then be connected to a hinge region that is connected to the CH2 domain. Alternatively, TL1A-CH1 may then be connected to a hinge region that is connected to the CH2 domain.

[0101] The CH2 region may contain a sequence selected from Tables 30, 31, 32, and 33. The CH2 domain may contain SEQ ID NO: 8. The first CH2 region and the second CH2 region may each contain the sequence shown in SEQ ID NO: 8. The CH2 region may be connected to the CH3 region.

[0102] The CH3 region may contain an array selected from Table 30, Table 31, Table 32 and Table 33. The CH3 region may contain an array selected from the group consisting of the arrays shown in SEQ ID NO: 9, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 180, SEQ ID NO: 183, SEQ ID NO: 155, SEQ ID NO: 158, SEQ ID NO: 185 and SEQ ID NO: 187. In some aspects, the CH3 region of the first Fc chain and the CH3 region of the second Fc chain each contain the sequence shown in SEQ ID NO: 9. In some aspects, the first Fc chain contains a first CH3 region, the second Fc chain contains a second CH3 region, the first CH3 region and the second CH3 region each contain different complementary sequences, and the different complementary sequences are the following pair of complementary sequences: (i) SEQ ID NO: 160 and SEQ ID NO: 162; (ii) SEQ ID NO: 180 and SEQ ID NO: 183; (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and (iv) SEQ ID NO: 185 and SEQ ID NO: 187 selected from.

[0103] In some embodiments using the knob-in-hole (KiH) method of hetero-dimerization, the first CH3 region and the second CH3 region contain SEQ ID NO: 160 and SEQ ID NO: 162 (including bispecific antibodies targeting TL1A and p40). In some embodiments using the knob-in-hole (KiH) method of hetero-dimerization, the first CH3 region and the second CH3 region contain SEQ ID NO: 185 and SEQ ID NO: 187 (the 185 / 187 pair is different from the 160 / 162 pair due to the absence of Cys residues). In some embodiments using the EEE / RRR, EE / RR or E / R method of hetero-dimerization, the first CH3 region and the second CH3 region contain SEQ ID NO: 180 and SEQ ID NO: 183 (including bispecific antibodies targeting TL1A and p40).

[0104] The TL1A antibody may contain a polypeptide having TL1A-VL. A polypeptide having TL1A-VL is a polypeptide containing TL1A-VL and one or more additional peptide regions such as one or more additional antibody domains. A standard IgG light chain (LC) containing TL1A-VL and CL is an example of a polypeptide having TL1A-VL. Representative polypeptides having TL1A-VL consisting essentially of TL1A-VL and CL include SEQ ID NO: 19 and SEQ ID NO: 202. The term polypeptide having TL1A-VL also includes polypeptides containing TL1A-VL and other protein domains / peptides (such as hinge, CH2 and / or CH3 domains). The LC-Fc of TL1A (see Table 31, Figure 8A and p40TL1A-0033) is an example of a polypeptide having TL1A-VL containing TL1A-VL fused to CL and then fused to a hinge domain, a CH2 domain and a CH3 domain. Representative polypeptides having TL1A-VL containing TL1A-VL, CL, a hinge domain, CH2 and CH3 include p40TL1A-0033 of SEQ ID NO: 205.

[0105] The TL1A antibody may contain a polypeptide having TL1A-VH. A polypeptide having TL1A-VH is a polypeptide containing one or more additional peptide regions such as TL1-VH and one or more additional antibody domains. A standard IgG heavy chain (HC) containing TL1A-VH, CH1, hinge domain, CH2, and CH3 is an example of a polypeptide having TL1A-VH. Representative polypeptides having TL1A-VH consisting essentially of TL1A-VH, CH1, hinge, CH2, and CH3 include the HC sequences from Table 30 such as SEQ ID NOs: 10, 23, 25, 27, 29, 34, 37, 40, 43, 45, 48, 50, 53, 55, 58, 60, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 111, 113, 115, 117, 119, 121, 123, 127, 132, 135, 138, 142, 144, 146, 150, 152, 154, and 172; Table 31: the HC sequences of TL1A from SEQ ID NOs: 184, 188, 192, 194, and 200; Table 32: the HC sequences of TL1A from SEQ ID NOs: 156, 161, 164, 165, and 166. The term polypeptide having TL1A-VH also includes polypeptides containing TL1A-VH and other domains / peptides (such as CH1 and / or only short peptides). The mFd of TL1A (see Table 31, Figure 8A, and p40TL1A-0033) is an example of a polypeptide containing TL1A-VH fused to CH1 and then fused to a short peptide derived from the upper IgG1 human hinge EPKSC and having TL1A-HL containing Cys at position H230 (SEQ ID NO: 206). Representative polypeptides having TL1A-VH containing TL1A-VH, CH1, and SEQ ID NO: 206 include p40TL1A-0033 of SEQ ID NO: 207.

[0106] The TL1A antibody may contain two identical light chains (two identical TL1A-LCs) and two identical heavy chains (two identical TL1A HCs). The TL1A-LC may contain TL1A-VL fused to the CL domain. The TL1A-HC may contain TL1A-VH which may contain a sequence selected from Tables 30, 31, 32 and 33. The TL1A-VH may contain a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% identical to a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 58, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 90, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 111, and SEQ ID NO: 121.

[0107] The polypeptide having TL1A-VL may contain a sequence selected from Tables 30, 31, 32 and 33. The polypeptide having TL1A-VL may contain a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence shown in SEQ ID NO: 19.

[0108] In some aspects, the TL1A antibody contains two identical Fab domains of TL1A. In some aspects of the present invention, the TL1A antibody contains two identical light chains and two identical heavy chains. In some aspects, the TL1A antibody contains two identical light chains having the sequence as shown in SEQ ID NO: 19. In some aspects, the TL1A antibody contains two identical heavy chains having the sequence as shown in SEQ ID NO: 43.

[0109] In some aspects, the TL1A antibody is characterized in that in a competitive ELISA, the IC 50 of TL1A is less than 20 nM. The TL1A antibody is the IC of TL1A in a competitive ELISA 50It may be characterized by being less than 10 nM. The TL1A antibody has an IC of TL1A in the TF-1 NFκB reporter cell bioassay 50 It may be characterized by being less than 50 nM. The TL1A antibody has an IC of TL1A in the TF-1 NFκB reporter cell bioassay 50 It may be characterized by being less than 30 nM. The TL1A antibody has an IC of TL1A in the whole blood IFNγ assay 50 It may be characterized by being less than 1 nM.

[0110] In some aspects, the TL1A antibody is bivalent and monospecific. A representative bivalent and monospecific Tl1A antibody contains the standard IgG format of two identical heavy chains and two identical light chains. Bivalent and monospecific TL1A antibodies are exemplified in Table 30. In some aspects, the antibody is characterized by having a score of less than 4 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay.

[0111] In some aspects, the TL1A antibody is a monovalent and monospecific antibody. Such an antibody is monospecific in that it can bind only to a single epitope or target, and is monovalent in that it has only a single binding domain.

[0112] The present disclosure provides examples of two different formats of monospecific and monovalent TL1A antibodies. The first format is a one-arm TL1A antibody, which contains a single Fab domain fused to a functional Fc domain, and the second format is an antibody containing a null arm, which is a TL1A antibody containing a TL1A-binding Fab domain and a second Fab domain that does not bind to TL1A or other known targets.

[0113] In some aspects, the TL1A antibody contains a one-armed antibody. A one-armed antibody is an IgG antibody that contains two hinge domains, two CH2 domains, and two CH3 domains, but contains an intact Fc domain with only one Fab region. A one-armed TL1A antibody is an IgG TL1A antibody that contains two hinge domains, two CH2 domains, and two CH3 domains, but contains an intact Fc domain with only one Fab region of TL1A. In some aspects, the TL1A antibody contains a monovalent and monospecific antibody. A one-armed TL1A antibody is monovalent and monospecific due to its single Fab domain for TL1A.

[0114] The one-armed antibody may contain a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain is the heavy chain described in the specification, the first light chain is as described in the specification, and the second heavy chain does not contain a VH domain or a CH1 domain.

[0115] The one-armed antibody may contain a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 161, SEQ ID NO: 164, and SEQ ID NO: 165, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163.

[0116] The one-armed antibody may contain a first heavy chain, a first light chain, and a second heavy chain, wherein the first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A, the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 161, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163.

[0117] The one-armed antibody may contain a first heavy chain, a first light chain, and a second heavy chain. The first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A. The first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 164. The first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19. The second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163.

[0118] The one-armed antibody may contain a first heavy chain, a first light chain, and a second heavy chain. The first heavy chain and the first light chain contain a TL1A binding site that binds to TL1A. The first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 165. The first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19. The second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 163.

[0119] In some aspects, the antibody contains a one-armed TL1A antibody and the half-life of the antibody is less than 7 days in cynomolgus monkeys. Such antibodies may be advantageous in applications where a shorter half-life is useful, such as in certain oncology applications and applications in discrete organs or compartments such as the eye.

[0120] In some aspects, the TL1A antibody contains a null arm. An antibody containing a null arm is a monovalent and monospecific antibody, and one of the antigen-binding sites is modified to eliminate binding to the target. In some aspects, the heavy chain CDR is modified to eliminate binding to the target. In some aspects, the light chain CDR is not modified. The null-armed TL1A antibody is a monovalent and monospecific TL1A antibody, and one of the antigen-binding sites is modified to eliminate binding to TL1A. In some aspects, one or more of the VH CDRs of TL1A are modified to eliminate binding to TL1A. A TL1A-VH containing one or more CDRs modified to eliminate TL1A binding may be designated as xTL1A-VH. In some aspects, the VL CDR of TL1A is not modified.

[0121] The null-arm TL1A antibody may contain a single TL1A-VH and a single xTL1A-VH, as well as two identical TL1A-VLs.

[0122] In some aspects, CDR-H1, CDR-H2, and CDR-H3 are each derived from TL1A-VH. The CDRs are derived from a TL1A-binding VH if the CDRs are made or produced by modifying the TL1A-binding VH by changing its amino acid sequence by a documented method in which at least one structural feature is retained in each method step.

[0123] In some aspects, the null-arm TL1A antibody contains an xTL1A-VH containing a sequence corresponding to a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153.

[0124] In some aspects, the antibody contains a null-arm TL1A antibody containing a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain that binds to TL1A (Fab of TL1A) (as described in the specification), and the second heavy chain and the second light chain contain a second Fab domain (Fab of xTL1A) containing a non-binding TL1A-binding domain that does not specifically bind to a target, and the first and second light chains are identical.

[0125] In some aspects, the Fab of xTL1A contains a VH containing a sequence corresponding to a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153. The Fab of xTL1A can be combined with the TL1A-VH described in the specification to create a null-arm TL1A antibody.

[0126] In some aspects, antibodies containing the Fab of TL1A and the Fab of xTL1A may be referred to as null-arm TL1A antibodies.

[0127] In some aspects, null-arm TL1A antibodies contain the sequences shown in Table 30. In some aspects, null-arm TL1A antibodies are selected from the group consisting of [xTL1A]-0336; [xTL1A]-0338; [xTL1A]-0341; [xTL1A]-0347; [xTL1A]-0349; [xTL1A]-0352; [xTL1A]-0358; [xTL1A]-0360; [xTL1A]-0363, as shown in Table 30. These antibodies may be made using a modified Fc domain, for example, alternative heterodimerization strategies such as LS mutations or KiH may be incorporated.

[0128] In some aspects, the antibody contains a null-arm TL1A antibody, and the second Fab domain contains a non-binding TL1A heavy chain variable region (xTL1A-VH) and a non-binding TL1A light chain variable region (xTL1A-VL), and contains the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 139; the sequence of CDR-H2 shown in SEQ ID NO: 140; the sequence of CDR-H3 shown in SEQ ID NO: 133; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 128; the sequence of CDR-H2 shown in SEQ ID NO: 129; the sequence of CDR-H3 shown in SEQ ID NO: 130; (iii) the sequence of CDR-H1 shown in SEQ ID NO: 128; the sequence of CDR-H2 shown in SEQ ID NO: 129; the sequence of CDR-H3 shown in SEQ ID NO: 133; (iv) the sequence of CDR-H1 shown in SEQ ID NO: 128; the sequence of CDR-H2 shown in SEQ ID NO: 129; the sequence of CDR-H3 shown in SEQ ID NO: 136; (v) the sequence of CDR-H1 shown in SEQ ID NO: 139; the sequence of CDR-H2 shown in SEQ ID NO: 140; the sequence of CDR-H3 shown in SEQ ID NO: 130; (vi) The sequence of CDR-H1 shown in SEQ ID NO: 139; the sequence of CDR-H2 shown in SEQ ID NO: 140; the sequence of CDR-H3 shown in SEQ ID NO: 136; (vii) The sequence of CDR-H1 shown in SEQ ID NO: 147; the sequence of CDR-H2 shown in SEQ ID NO: 148; the sequence of CDR-H3 shown in SEQ ID NO: 130; (viii) The sequence of CDR-H1 shown in SEQ ID NO: 147; the sequence of CDR-H2 shown in SEQ ID NO: 148; the sequence of CDR-H3 shown in SEQ ID NO: 133; or, (ix) The sequence of CDR-H1 shown in SEQ ID NO: 147; the sequence of CDR-H2 shown in SEQ ID NO: 148; the sequence of CDR-H3 shown in SEQ ID NO: 136 contains.

[0129] In some aspects, the antibody contains a null-arm TL1A antibody, the second Fab domain contains a heavy chain variable region (xTL1A-VH) and a light chain variable region (xTL1A-VL), the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and, the sequence of CDR-L3 shown in SEQ ID NO: 13, and the sequence of CDR-H1 shown in SEQ ID NO: 139; the sequence of CDR-H2 shown in SEQ ID NO: 140; the sequence of CDR-H3 shown in SEQ ID NO: 133.

[0130] In some aspects, the antibody contains a null-arm TL1A antibody, the second Fab domain contains the light chain variable amino acid sequence shown in SEQ ID NO: 18, and the second Fab domain contains a sequence selected from the group consisting of the heavy chain variable amino acid sequences shown in SEQ ID NO: 143, SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 149, SEQ ID NO: 151, and SEQ ID NO: 153.

[0131] In some aspects, the antibody contains a null-arm TL1A antibody, the second Fab domain contains the light chain variable amino acid sequence shown in SEQ ID NO: 18, and the second Fab domain contains the heavy chain variable amino acid sequence shown in SEQ ID NO: 143.

[0132] In some aspects, the antibody comprises a null-arm TL1A antibody comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (Fab of TL1A) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (Fab of xTL1A) that comprises a non-binding TL1A binding domain that does not specifically bind to a target, the first antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 19, and the second antibody heavy chain comprises a sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NO: 166.

[0133] In some aspects, the antibody comprises a null-arm TL1A antibody comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (Fab of TL1A) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (Fab of xTL1A) that comprises a non-binding TL1A binding domain that does not specifically bind to a target, the first antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence set forth in SEQ ID NO: 19, and the second antibody heavy chain comprises a sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NO: 166.

[0134] In some aspects, the antibody contains a null-arm TL1A antibody containing a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain contain a first Fab domain that binds to TL1A (Fab of TL1A), and the second heavy chain and the second light chain contain a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to the target (Fab of xTL1A), the first antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 161, the first antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, the second antibody light chain contains the amino acid sequence shown in SEQ ID NO: 19, and the second antibody heavy chain contains the amino acid sequence shown in SEQ ID NO: 166.

[0135] The null-arm TL1A antibody may be characterized in that it is a high molecular weight species with a score of less than 2% as determined by analytical size exclusion chromatography (aSEC). The aSEC assay may be performed as described in the examples.

[0136] The null-arm TL1A antibody may be characterized in that it has a score of less than 7 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay. The null-arm TL1A antibody may be characterized in that it has a score of less than 6 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay. The null-arm TL1A antibody may be characterized in that it has a score of less than 5 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay.

[0137] The null-arm TL1A antibody may be characterized in that it has a score of less than 4 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay. The null-arm TL1A antibody may be characterized in that it has a score of less than 3 in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay. The AC-SINS assay may be performed as described in the examples.

[0138] The null-arm TL1A antibody may be characterized by having an IC50 of less than 2 nM in the NFκB TL1A neutralization bioassay. The calculation of the IC50 in the NFκB TL1A neutralization bioassay may be performed as described in the examples.

[0139] In some aspects, the null-arm TL1A antibody binds to cynomolgus TL1A within an order of magnitude of human TL1A as measured by SPR. In some aspects, the null-arm TL1A antibody binds to human TL1A with at least 500-fold higher affinity than mouse T1A as measured by SPR. In some aspects, the null-arm TL1A antibody binds to human TL1A with at least 2000-fold higher affinity than mouse T1A as measured by SPR. The null-arm TL1A antibody may be characterized by having a KD of less than 500 pM as measured by SPR. The null-arm TL1A antibody may be characterized by having a KD of less than 320 pM as measured by SPR. The null-arm TL1A antibody may be characterized by having a KD of less than 300 pM as measured by SPR. The individual SPR assays may be performed as described in the examples.

[0140] The half-life of the null-arm TL1A antibody may be characterized by being at least 21 days in cynomolgus monkeys. The half-life of the null-arm TL1A antibody may be characterized by being at least 25 days in cynomolgus monkeys. The half-life of the null-arm TL1A antibody may be characterized by being at least 28 days in cynomolgus monkeys.

[0141] The half-life of the null-arm TL1A antibody may be characterized by being 21 to 45 days in cynomolgus monkeys. The half-life of the null-arm TL1A antibody may be characterized by being 25 to 35 days in cynomolgus monkeys. The half-life of the null-arm TL1A antibody may be characterized by being 28 to 30 days in cynomolgus monkeys.

[0142] Antibody against p40 The present disclosure provides antibodies that bind to p40. The anti-p40 antibodies of the invention may bind to one or more additional targets. P40 is also known as IL12B, CLMF, CLMF2, IL-12B, IMD28, NKSF, NKSF2, and IMD29. As used herein, the term "p40" includes one or more variants, isoforms, homologs, orthologs, and paralogs of p40. In some embodiments, the antibodies disclosed herein cross-react with p40 from non-human species, such as cynomolgus monkey p40, and different forms of p40. In some embodiments, the antibody may be completely specific for human p40 and may not exhibit species cross-reactivity or other types of cross-reactivity. As used herein, the term "p40" refers to naturally occurring human p40, unless otherwise indicated by context. "P40 antibody", "anti-p40 antibody", or other similar designations mean an antibody (as defined in the specification) that binds or reacts with p40, its isoform, fragment, or derivative. The full-length mature form of p40 is represented by UniProtKB / Swiss-Prot accession number P29460. The full-length mature form of cynomolgus monkey p40 is represented by UniProtKB / Swiss-Prot accession number G7P6S2.

[0143] The p40 antibody may contain a framework sequence of p40-VH that contains a framework sequence of VH of the human germline. The framework sequence of p40-VH may contain one or more amino acid substitutions, additions or deletions while still retaining functional and structural similarity to the germline from which it is derived. In some aspects, the framework sequence of VH is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the framework sequence of VH of the human germline. In some aspects, the p40 antibody contains a framework sequence of p40-VH that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the framework sequence of VH of the human germline. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on similarity to VH excluding the portions defined as CDRs in this specification.

[0144] The present disclosure provides an isolated antibody that specifically binds to p40 via a p40 binding domain, the antibody containing at least one additional antigen binding domain that specifically binds to TL1A, the p40 binding domain containing a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL) containing the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NO: 171 and the sequences of CDR-L1, CDR-L2 and CDR-L3 shown in SEQ ID NO: 177.

[0145] The present disclosure provides an isolated antibody that specifically binds to p40 via a p40-binding domain, the antibody contains a TL1A antigen-binding domain that specifically binds to TL1A, the p40-binding domain contains a heavy-chain variable region (p40-VH) and a light-chain variable region (p40-VL), the CDR-H1 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 167; the CDR-H2 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 168; the CDR-H3 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 169; the CDR-L1 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 173; the CDR-L2 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 174; the CDR-L3 of the p40-binding domain contains the amino acid sequence shown in SEQ ID NO: 175.

[0146] In some aspects, the framework sequence of p40-VH may be derived from a human germline VH sequence selected from the group consisting of DP3, DP7, DP73, DP75, and DP88. In some aspects, the framework sequence of p40-VH is derived from DP73.

[0147] The framework sequence of p40-VH may be derived from a human germline VH sequence selected from the group consisting of IGHV5-51*01 / 5-51*03, IGHV1-46*01 / 1-46*03, IGKV1-39*01, IGHV5-51*02, IGHV5-51*04, IGHV1-46*02, IGHV1-69-2*01, IGHV1-69*08, IGHV1-69*02, IGHV1-69*06 / 1-69*14, IGHV1-69*04 / 1-69*09, and IGHV1-2*02. In some aspects, the framework sequence of p40-VH is derived from IGHV5-51*01 / 5-51*03.

[0148] The present invention identified a human germline for IGHV5-51*01 / 5-51*03 (DP-73) as being very advantageous relative to the p40-VH CDR of the present invention. Experimental data show that V LIt is demonstrated that IGHV1-46*01 / 1-46*03 (DP-7) and IGKV1-39*01 or DPK9 (with L46S mutation) and VK1-33 (with L46S mutation) were advantageously able to retain binding within about 3 to 4-fold after grafting. Other germline sequences that may be suitable for use with the p40-VH CDR of the present invention include other IGHV5-51 locus germline sequences IGHV5-51*02 and IGHV5-51*04, other IGHV1-46 locus germline sequences such as IGHV1-46*02, IGHV1-69-2*01 (DP-3), and other IGHV1-69 locus germline sequences IGHV1-69*08, IGHV1-69*02, IGHV1-69*06 / 1-69*14 (DP-88), IGHV1-69*04 / 1-69*09 and IGHV1-2*02 (DP-75). The aforementioned frameworks are modeled to be compatible with the p40-VH CDR of the present invention.

[0149] The p40 antibody may contain the framework sequence of p40-VL that contains the framework sequence of the VL of the human germline. The framework sequence of p40-VL may contain one or more amino acid substitutions, additions or deletions while still retaining the functional and structural similarity to the germline from which it is derived. In some aspects, the framework of VL is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the framework sequence of the VL of the human germline. In some aspects, the p40 antibody contains the framework sequence of p40-VL that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions with respect to the framework sequence of the VL of the human germline. In some aspects, the 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on the similarity to VL excluding the portion defined as CDR in this specification.

[0150] In some aspects, the p40-VL framework array may be derived from a human germline VL sequence selected from the group consisting of DPK4, DPK5, DPK7, DPK8, and DPK9. In some aspects, the p40-VL framework sequence is derived from DPK7.

[0151] The p40-VL framework sequence may be derived from a human germline VL sequence selected from the group consisting of IGKV1D-16*01, IGKV1D-16*02, IGKV1-16*01, IGKV1-16*02, IGKV1-39*01, IGKV1-12*01 / 1-12*02 / 1D-12*01 / 1D-12*02, IGKV1-9*01, IGKV1-5*03, IGKV1-5*01, and IGKV1-27*01. In some aspects, the p40-VL framework sequence is derived from IGKV1D-16*01.

[0152] The present invention has identified the human germline VL framework IGKV1D-16*01 (DPK7) as being very advantageous with the p40-VL CDR of the present invention. Advantageously, other germline VLs that may be used with the p40-VL region of the present invention include other IGKV1D-16 locus germline sequences IGKV1D-16*02, IGKV1-16*01, IGKV1-16*02, IGKV1-39*01 (DPK9), IGKV1-12*01 / 1-12*02 / 1D-12*01 / 1D-12*02 (DPK5), IGKV1-9*01 (DPK8), IGKV1-5*03, IGKV1-5*01, IGKV1-27*01 (DPK4). The foregoing frameworks are modeled to be compatible with the p40-VL CDR of the present invention.

[0153] In some aspects of the present disclosure, the p40-CH1 of the antibody contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. In some aspects of the present disclosure, the p40-CL of the antibody contains a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. The p40-CH1 may contain the sequence shown in SEQ ID NO: 6. The p40-CL may contain the sequence shown in SEQ ID NO: 16. The p40-CH1 and p40-CL may each be part of a bispecific antibody.

[0154] The p40-CH1 may be connected to the p40-VH, and the p40-CL may be connected to the p40-VL, forming a p40-binding Fab domain (Fab of p40).

[0155] The p40 antibody of the present invention may contain a hinge region. The hinge region may be selected from any suitable sequence, including the sequences selected from Table 31 and Table 33. In some aspects, the hinge region is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206.

[0156] The p40-CL may be connected to a hinge region that is then connected to the CH2 domain. Alternatively, the p40-CH1 may be connected to a hinge region that is then connected to the CH2 domain. The CH2 domain may contain SEQ ID NO: 8. The CH2 region may be connected to the CH3 region. The CH3 region may contain a sequence selected from Table 31 and Table 33. The CH3 region may contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 9, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 180, SEQ ID NO: 183, SEQ ID NO: 155, SEQ ID NO: 158, SEQ ID NO: 185, and SEQ ID NO: 187. In some aspects, the first Fc chain contains the first CH3 region, the second Fc chain contains the second CH3 region, the first CH3 region and the second CH3 region each contain different complementary sequences, and the different complementary sequences are one of the following pairs of complementary sequences: (i) SEQ ID NO: 160 and SEQ ID NO: 162; (ii) SEQ ID NO: 180 and SEQ ID NO: 183; (iii) SEQ ID NO: 155 and SEQ ID NO: 158; (iv) SEQ ID NO: 185 and SEQ ID NO: 187 is selected from.

[0157] In some aspects, the first CH3 region and the second CH3 region contain SEQ ID NO: 160 and SEQ ID NO: 162.

[0158] The polypeptide having p40-VH may contain a sequence selected from Tables 31 and 33. The polypeptide having p40-VH may contain a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 181, SEQ ID NO: 186, SEQ ID NO: 190, SEQ ID NO: 193, SEQ ID NO: 196 and SEQ ID NO: 203.

[0159] The polypeptide having p40-VL may contain a sequence selected from Tables 31 and 33. The polypeptide having p40-VL may contain a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 178 and SEQ ID NO: 198.

[0160] In some aspects, the present disclosure provides an isolated bispecific antibody that specifically binds to p40 via a p40 binding domain and specifically binds to TL1A via a TL1A binding domain, wherein the p40 binding domain contains a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), the p40-VH contains the sequences of CDR-H1, CDR-H2, and CDR-H3 encoded by a plasmid deposited with the ATCC under accession number PTA-127206, and the p40-VL contains the sequences of CDR-L1, CDR-L2, and CDR-L3 encoded by a plasmid deposited with the ATCC under accession number PTA-127205.

[0161] In some aspects, the present disclosure provides a p40 antibody containing the sequence of p40-VH encoded by a plasmid deposited with the ATCC under accession number PTA-127206 and the sequence of p40-VL encoded by a plasmid deposited with the ATCC under accession number PTA-127205.

[0162] In some aspects, the present disclosure provides a p40 antibody containing a polypeptide sequence having p40-VH encoded by a plasmid deposited with the ATCC under accession number PTA-127204. In some aspects, the present disclosure provides a p40 antibody containing a polypeptide sequence having p40-VL encoded by a plasmid deposited with the ATCC under accession number PTA-127203.

[0163] Antibodies against TL1A and p40 The present disclosure provides antibodies that bind to TL1A and p40. As used herein, the terms TL1A and p40 include variants, isoforms, homologs, orthologs, and paralogs of TL1A and p40, respectively. In some embodiments, the antibodies disclosed herein cross-react with one or more of TL1A and p40 from non-human species such as cynomolgus monkey TL1A and p40. In some embodiments, the antibody may be completely specific for TL1A and p40 and may not exhibit species cross-reactivity or other types of cross-reactivity. As used herein, the terms TL1A and p40 refer to naturally occurring human TL1A and p40 unless otherwise indicated by context. "TL1A / p40 antibody", "anti-TL1A / p40 antibody", or other similar designations mean an antibody (as defined herein) that binds or reacts with TL1A and p40, its isoforms, fragments, or derivatives.

[0164] In some embodiments, the invention provides a TL1A / p40 antibody having a light chain variable region (VL) sequence and a heavy chain variable region (VH) sequence or a variant thereof found in one or more of Tables 30, 31, 32, and 33.

[0165] The invention also provides the CDR portions of the TL1A / p40 antibody. The CDR regions are defined in FIG. 10. In some embodiments, the TL1A / p40 antibody contains six CDRs of a TL1A antibody selected from Tables 30, 31, 32, and 33. In some embodiments, the antibody contains the VH and VL of a TL1A antibody selected from Tables 30, 31, 32, and 33. In some embodiments, the TL1A / p40 antibody contains a sequence selected from Tables 30, 31, 32, and 33.

[0166] In some embodiments, the present disclosure provides anti-TL1A / p40 antibodies containing variant forms of the CDR, VH, VL, HC, and LC regions shown in one or more of Tables 30, 31, 32, and 33, where such variant polypeptides have at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with the amino acid sequences disclosed in one or more of Tables 30, 31, 32, and 33. These amounts are not intended to be limiting, and increases in the recited percentages are specifically contemplated as part of this disclosure.

[0167] The present disclosure provides an isolated antibody containing a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site contains a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), the second antigen-binding site contains a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), the p40-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and the sequence of CDR-L3 shown in SEQ ID NO: 175; and the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and the sequence of CDR-H3 shown in SEQ ID NO: 169, and the TL1A-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (iii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 32; (iv) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (v) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (vi) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (vii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (viii) The sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 35; (ix) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (x) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xi) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xii) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xiii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 31; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xiv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 38; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xvi) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xvii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xviii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xix) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xx) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xxi) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; and, (xxii) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; Provided is an antibody further containing a combination of heavy chain CDRs selected from the above.

[0168] In some aspects, the present disclosure provides an isolated antibody containing a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site contains a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), the second antigen-binding site contains a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and, (i) The p40-binding domain contains the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and, the sequence of CDR-L3 shown in SEQ ID NO: 175; and, the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and, the sequence of CDR-H3 shown in SEQ ID NO: 169, and, (ii) The TL1A-binding domain contains the sequences of CDR-L1 shown in SEQ ID NO: 11, the sequences of CDR-L2 shown in SEQ ID NO: 12, and the sequences of CDR-L3 shown in SEQ ID NO: 13, and also contains the sequences of CDR-H1 shown in SEQ ID NO: 30, the sequences of CDR-H2 shown in SEQ ID NO: 41, and the sequences of CDR-H3 shown in SEQ ID NO: 32. It provides an antibody.

[0169] In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VH derived from a VH sequence of a human germline selected from the group consisting of IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02. In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VH derived from the sequence of the human IGHV1-18*01 germline.

[0170] In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VL derived from a VL sequence of a human germline selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01. In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VL derived from the sequence of the human germline IGKV1-39*01.

[0171] In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VL and the framework sequence of TL1A-VH, and one or both of the framework sequence of TL1A-VL and the framework sequence of TL1A-VH are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of the human germline from which it is derived.

[0172] In some aspects, the TL1A / p40 antibody contains the framework sequence of TL1A-VL and the framework sequence of TL1A-VH, and one or both of the framework sequence of TL1A-VL or the framework sequence of TL1A-VH are identical to the sequence of the human germline from which it is derived.

[0173] In some aspects, TL1A-VL contains the amino acid sequence shown in SEQ ID NO: 18, and TL1A-VH contains a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120.

[0174] In some aspects, the TL1A / p40 antibody contains a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 42 and a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 18.

[0175] In some aspects, the TL1A / p40 antibody contains the TL1A-VH sequence shown in SEQ ID NO: 42 and the TL1A-VL shown in SEQ ID NO: 18.

[0176] In some aspects, the TL1A / p40 antibody contains the sequence of TL1A-VH encoded by the nucleic acid sequence shown in SEQ ID NO: 228. In some aspects, the TL1A / p40 antibody contains the sequence of TL1A-VL encoded by the nucleic acid sequence shown in SEQ ID NO: 229.

[0177] In some aspects, the TL1A / p40 antibody contains the sequence of TL1A-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127347. In some aspects, the TL1A / p40 antibody contains the sequence of TL1A-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127348. In some aspects, the TL1A / p40 antibody contains the sequence of TL1A-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127347 and the sequence of TL1A-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127348.

[0178] In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VH derived from the VH sequence of a human germline selected from the group consisting of DP3, DP7, DP73, DP75, and DP88. In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VH derived from the sequence of the human DP73 germline. In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VL derived from the VL sequence of a human germline selected from the group consisting of DPK4, DPK5, DPK7, DPK8, and DPK9. In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VL derived from the DPK9 sequence of the human germline.

[0179] In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VL and the framework sequence of p40-VH, and one or both of the framework sequence of p40-VL and the framework sequence of p40-VH are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of the human germline from which it is derived. In some aspects, the TL1A / p40 antibody contains the framework sequence of p40-VL and the framework sequence of p40-VH, and one or both of the framework sequence of p40-VL or the framework sequence of p40-VH are identical to the sequence of the human germline from which it is derived.

[0180] In some aspects, the TL1A / p40 antibody contains a p40-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 177 and a p40-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 171.

[0181] In some aspects, p40-VL contains the amino acid sequence shown in SEQ ID NO: 177 and p40-VH contains the amino acid sequence shown in SEQ ID NO: 171.

[0182] In some aspects, the TL1A / p40 antibody contains a p40-VH sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 238.

[0183] In some aspects, the TL1A / p40 antibody contains a p40-VL sequence encoded by the nucleic acid sequence shown in SEQ ID NO: 239.

[0184] In some aspects, the TL1A / p40 antibody contains the sequence of p40-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127206. In some aspects, the TL1A / p40 antibody contains the sequence of p40-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127205. In some aspects, the TL1A / p40 antibody contains the sequence of p40-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127206 and the sequence of p40-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127205.

[0185] In some aspects, the TL1A / p40 antibody contains TL1A-VH (TL1A-CH1) fused to the CH1 domain, and TL1A-VL is fused to the light chain constant domain (TL1A-CL) to form a TL1A-binding Fab domain (Fab of TL1A). TL1A-CH1 may contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. TL1A-CH1 may contain the sequence shown in SEQ ID NO: 6. TL1A-CL may contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. TL1A-CL may contain the sequence shown in SEQ ID NO: 16.

[0186] In some aspects, the TL1A / p40 antibody contains p40-VH (p40-CH1) fused to the CH1 domain and p40-VL (p40-CL) fused to the light chain constant domain to form a p40-binding Fab domain (Fab of p40). p40-CH1 may contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. p40-CH1 may contain the sequence shown in SEQ ID NO: 6. p40-CL may contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. p40-CL may contain the sequence shown in SEQ ID NO: 16.

[0187] In some aspects, the TL1A / p40 antibody contains an antibody Fc domain containing a first Fc chain and a second Fc chain. The Fc domain may be an Fc domain of IgA (e.g., IgA 1 or IgA 2 ), IgD, IgE, IgM or IgG (e.g., IgG 1 , IgG 2 , IgG 3 or IgG 4 ). In some aspects, the Fc domain is an Fc domain of IgG 1 .

[0188] In some aspects, the TL1A / p40 antibody contains a first Fc chain containing a first hinge region, a first CH2 region and a first CH3 region from the N-terminus to the C-terminus, and a second Fc chain containing a second hinge region, a second CH2 region and a second CH3 region from the N-terminus to the C-terminus. In some aspects, the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain. In some aspects, the N-terminus of the second Fc chain is connected to the C-terminus of the first p40-CH1 domain. In some aspects, the first CH2 region and the second CH2 region each contain the sequence shown in SEQ ID NO: 8.

[0189] In some aspects, either or both of the first hinge regions contain a sequence selected from the group consisting of the sequences shown in SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182 and SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204 and SEQ ID NO: 206. In some aspects, the first hinge region and the second hinge region each contain one or more amino acid modifications that promote the association of the first hinge region and the second hinge region.

[0190] In some aspects, the first hinge region and the second hinge region each contain different complementary sequences, and the different complementary sequences are the following pair of complementary sequences: (i) SEQ ID NO: 179 and SEQ ID NO: 182; (EEE), and (ii) SEQ ID NO: 189 and SEQ ID NO: 191 (EE) is selected from

[0191] The first hinge region may contain the sequence shown in SEQ ID NO: 204. The second hinge region may contain the sequence shown in SEQ ID NO: 7.

[0192] In some aspects, the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote the association of the first Fc chain and the second Fc chain. The first Fc chain may contain a first CH3 region, the second Fc chain may contain a second CH3 region, the first CH3 region and the second CH3 region each contain different complementary sequences, and the different complementary sequences are one of the following pairs of complementary sequences: (i) SEQ ID NO: 160 and SEQ ID NO: 162; (ii) SEQ ID NO: 180 and SEQ ID NO: 183; (EEE, EE, E) (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and (iv) SEQ ID NO: 185 and SEQ ID NO: 187 is selected from

[0193] When the first and second CH3 domains contain SEQ ID NO: 160 and SEQ ID NO: 162, these CH3 domains function well with complementary hinge pairs of SEQ ID NO: 179 and SEQ ID NO: 182 (EEE / RRR hetero-dimerization strategy), or SEQ ID NO: 189 and SEQ ID NO: 191 (EE / RR hetero-dimerization strategy).

[0194] In some aspects, the TL1A / p40 antibody contains the Fab of TL1A, and TL1A-CL is covalently fused to the first hinge region. In some aspects, TL1A-CL is covalently fused to the first Fc chain. In some aspects, TL1A-CL is covalently fused to the first Fc chain via the first hinge region.

[0195] In some aspects, the TL1A / p40 antibody contains first, second, third, and fourth polypeptide chains, where the first and third polypeptide chains together form the Fab of TL1A, and the second and fourth polypeptide chains together form the Fab of p40. In some aspects, the first, second, third, and fourth polypeptide chains are (i) the sequence of the first polypeptide is as set forth in SEQ ID NO: 205, the sequence of the second polypeptide is as set forth in SEQ ID NO: 203, the sequence of the third polypeptide is as set forth in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 178; (ii) the sequence of the first polypeptide is as set forth in SEQ ID NO: 188, the sequence of the second polypeptide is as set forth in SEQ ID NO: 186, the sequence of the third polypeptide is as set forth in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 178; (iii) the sequence of the first polypeptide is as set forth in SEQ ID NO: 192, the sequence of the second polypeptide is as set forth in SEQ ID NO: 190, the sequence of the third polypeptide is as set forth in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 178; (iv) the sequence of the first polypeptide is as set forth in SEQ ID NO: 194, the sequence of the second polypeptide is as set forth in SEQ ID NO: 193, the sequence of the third polypeptide is as set forth in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 178; or (v) the sequence of the first polypeptide is as set forth in SEQ ID NO: 200, the sequence of the second polypeptide is as set forth in SEQ ID NO: 196, the sequence of the third polypeptide is as set forth in SEQ ID NO: 202, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 198; and has a combination of sequences according to one of the groups selected from

[0196] In some aspects, the TL1A / p40 antibody contains a first polypeptide sequence as set forth in SEQ ID NO: 205, a second polypeptide as set forth in SEQ ID NO: 203, a third polypeptide as set forth in SEQ ID NO: 207, and a fourth polypeptide as set forth in SEQ ID NO: 178.

[0197] In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, the antibody comprising first, second, third, and fourth polypeptide chains, wherein the first and third polypeptide chains together form a TL1A binding region, the second and fourth polypeptide chains together form a p40 binding region, and the sequence of the first polypeptide is as set forth in SEQ ID NO: 205, the sequence of the second polypeptide is as set forth in SEQ ID NO: 203, the sequence of the third polypeptide is as set forth in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as set forth in SEQ ID NO: 178.

[0198] In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, the antibody comprising first, second, third, and fourth polypeptide chains, wherein the first and third polypeptide chains together form a TL1A binding region, the second and fourth polypeptide chains together form a p40 binding region, and the sequence of the first polypeptide comprises the sequence encoded by the plasmid deposited with the ATCC under accession number PTA-127349, the sequence of the second polypeptide comprises the sequence encoded by the plasmid deposited with the ATCC under accession number PTA-127346, the sequence of the third polypeptide comprises the sequence encoded by the plasmid deposited with the ATCC under accession number PTA-127350, and the sequence of the fourth polypeptide comprises the sequence encoded by the plasmid deposited with the ATCC under accession number PTA-127203.

[0199] In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40 and contains the CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40 and contains the VH and VL of an antibody that binds to TL1A selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40 and is selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40 and contains the CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40 and contains the VH and VL of an antibody selected from one or more of Tables 30, 31, 32, and 33.

[0200] In some aspects, the TL1A / p40 antibody is characterized in that the score in the affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 2. The AC-SINS assay may be performed as described in the examples.

[0201] In some aspects, the TL1A / p40 antibody is characterized in that at least 50% of the charge heterogeneity of the antibody is non-acidic and non-basic when measured by antibody imaging capillary electrophoresis (iCE) of a stress-free sample (T0) to be evaluated. The measurement of non-acidic and non-basic species by iCE may be performed as described in the examples.

[0202] In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 500 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 300 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 1 nM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 900 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 600 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds simultaneously to p40 (IL-23) and TL1A in an SPR assay, where the antibody is injected onto immobilized TL1A and the resulting complex is then treated with IL-23. SPR may be performed as described in the Examples.

[0203] In some aspects, the TL1A / p40 antibody has an IC 50 of less than 5 nM in a human IL-12 neutralization Kit-225 assay. The antibody may have an IC 50 of less than 4 nM in a human IL-12 neutralization Kit-225 assay. The antibody may have an IC 50 of less than 2 pM in a human IL-12 neutralization Kit-225 assay. The antibody has an IC 50 of less than 5 nM in a human IL-23 neutralization Kit-225 assay. The antibody has an IC 50 of less than 4 nM in a human IL-23 neutralization Kit-225 assay. The antibody has an IC 50 of less than 1 nM in a human IL-23 neutralization Kit-225 assay in human whole blood. The antibody has an IC 50It may be characterized in that it is less than 0.5 nM. In some aspects, the Kit-225 assay is in human whole blood. Each individual Kit-225 assay may be performed as described in the examples for that individual assay.

[0204] In some aspects, the TL1A / p40 antibody has an IC 50 less than 5 nM in the cynomolgus IL-23 neutralizing Kit-225 assay. The antibody may be characterized in that it has an IC 50 less than 2 nM in the cynomolgus IL-12 neutralizing Kit-225 assay. The antibody may be characterized in that it has an IC 50 less than 1 nM in the cynomolgus IL-12 neutralizing Kit-225 assay. Each individual Kit-225 assay may be performed as described in the examples for that individual assay.

[0205] The antibody has an IC 50 less than 2 nM in the human whole blood assay measuring inhibition of IFNγ. The antibody has an IC 50 less than 3 nM in the human whole blood assay measuring inhibition of IFNγ. The antibody has an IC 50 less than 2 nM in the human whole blood assay measuring inhibition of IFNγ. The antibody has an IC 50 less than 500 pM in the isolated human CD4+ cell assay measuring inhibition of IFNγ. The antibody has an IC 50 less than 100 pM in the isolated human CD4+ cell assay measuring inhibition of IFNγ. The antibody has an IC 50 less than 200 nM in the human NFκB neutralizing assay in TF-1 reporter cells. The antibody has an IC 50It may be characterized by being less than 150 nM. The individual IC-50 assays referred to in this paragraph may be performed as described in the Examples for each individual assay.

[0206] In some aspects, the half-life of the TL1A / p40 antibody is characterized by being at least 10 days in TG32 mice in a two-week analysis. In some aspects, the half-life is at least 14 days in TG32 mice in a two-week analysis. In some aspects, the half-life is at least 16 days in TG32 mice in a two-week analysis. In some aspects, the half-life is at least 17 days in TG32 mice in a two-week analysis. In some aspects, the half-life of the TL1A / p40 antibody is characterized by being at least 21 days in cynomolgus monkeys. In some aspects, the half-life is at least 25 days in cynomolgus monkeys. In some aspects, the half-life is at least 28 days in cynomolgus monkeys. The assays for determining the individual half-lives in TG32 mice and cynomolgus monkeys may be performed as described in the Examples for each individual assay.

[0207] In some aspects, the present disclosure provides an isolated anti-TL1A / p40 antibody that specifically binds to TL1A via a TL1A heavy chain variable region (TL1A-VH) and a TL1A light chain variable region (TL1A-VL), and specifically binds to p40 via a p40 heavy chain variable region (p40-VH) and a p40 light chain variable region (p40-VL), wherein the TL1A-VH contains the sequences of CDR-H1, CDR-H2 and CDR-H3 encoded by the plasmid deposited with the ATCC under accession number PTA-127347, the TL1A-VL contains the sequences of CDR-L1, CDR-L2 and CDR-L3 encoded by the plasmid deposited with the ATCC under accession number PTA-127348, the p40-VH contains the sequences of CDR-H1, CDR-H2 and CDR-H3 encoded by the plasmid deposited with the ATCC under accession number PTA-127206, and the p40-VL contains the sequences of CDR-L1, CDR-L2 and CDR-L3 encoded by the plasmid deposited with the ATCC under accession number PTA-127205.

[0208] In some aspects, the present disclosure provides an isolated anti-TL1A / p40 antibody that specifically binds to TL1A via a TL1A heavy chain variable region (TL1A-VH) and a TL1A light chain variable region (TL1A-VL), and specifically binds to p40 via a p40 heavy chain variable region (p40-VH) and a p40 light chain variable region (p40-VL), and contains the sequence of TL1A-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127347, and the sequence of TL1A-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127348; as well as the sequence of p40-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127206, and the sequence of p40-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127205.

[0209] In some aspects, the present disclosure provides an isolated anti-TL1A / p40 antibody containing the sequences encoded by the plasmids deposited with the ATCC under accession number PTA-127203; the sequences encoded by the plasmids deposited with the ATCC under accession number PTA-127346; the sequences encoded by the plasmids deposited with the ATCC under accession number PTA-127349; and the sequences encoded by the plasmids deposited with the ATCC under accession number PTA-127350.

[0210] Nucleic acid The present disclosure also provides a polynucleotide encoding an antibody of the invention, including a portion of the antibodies described herein and modified antibodies. The present invention also provides methods for producing the antibodies or polynucleotides described herein. The polynucleotides can be produced by procedures known in the art and can express proteins.

[0211] If desired, the antibody of interest (monoclonal or polyclonal) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained in a vector in a host cell, which may then be grown and frozen for future use. The production of recombinant monoclonal antibodies in cell culture can be performed by cloning antibody genes from B cells by means known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329, 112; U.S. Patent No. 7,314,622.

[0212] In some embodiments, polynucleotides containing sequences encoding either or both of the heavy or light chain variable regions of the antibodies provided herein are provided herein. The sequence encoding the antibody of interest may be maintained in a vector in a host cell, which may then be grown and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

[0213] In some aspects, the present disclosure provides a polynucleotide encoding the amino acid sequence of an antibody listed in one or more of Tables 30, 31, 32, and 33. The polynucleotide may be RNA. The polynucleotide may contain at least one chemical modification. The chemical modification may be selected from the group consisting of pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine, and 2'-O-methyluridine.

[0214] In some aspects, the polynucleotide does not contain a chemical modification.

[0215] In some aspects, an isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to TL1A, wherein the nucleic acid contains the nucleic acid sequence set forth in SEQ ID NO: 228, the nucleic acid sequence set forth in SEQ ID NO: 229, or both, is provided.

[0216] E196. A polynucleotide encoding a polypeptide having VH of an antibody that binds to TL1A and a polypeptide having VL or both, wherein the nucleic acid contains the nucleic acid sequence set forth in SEQ ID NO: 231, the nucleic acid sequence set forth in SEQ ID NO: 233, or both.

[0217] In some aspects, there is provided an isolated polynucleotide encoding the VH, VL, or both of an antibody that binds to TL1A, wherein the nucleic acid contains the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127347, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127348, or both.

[0218] In some aspects, there is provided a polypeptide having the VH of an antibody that binds to TL1A and the VL of an antibody that binds to TL1A, or both, wherein the nucleic acid contains the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127347, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127348, or both.

[0219] In some aspects, there is provided an isolated polynucleotide containing one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody contains a null-arm TL1A antibody containing a first variable heavy chain and a first variable light chain, and a second variable heavy chain and a second variable light chain, wherein the first variable heavy chain and the first variable light chain contain a first Fab domain that binds to TL1A (Fab of TL1A), and the second variable heavy chain and the second variable light chain contain a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to a target (Fab of xTL1A), and the first and second variable light chains are identical, and the polynucleotide contains the nucleic acid sequence set forth in SEQ ID NO: 228, the nucleic acid sequence set forth in SEQ ID NO: 230, and / or the nucleic acid sequence set forth in SEQ ID NO: 260.

[0220] In some aspects, an isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody comprises a null-arm TL1A antibody comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (Fab of TL1A), and the second heavy chain and the second light chain comprise a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to a target (Fab of xTL1A), wherein the first and second light chains are identical, and the polynucleotide comprises the nucleic acid sequence set forth in SEQ ID NO: 231, the nucleic acid sequence set forth in SEQ ID NO: 232, and / or the nucleic acid sequence set forth in SEQ ID NO: 233, a polynucleotide is provided.

[0221] In some aspects, an isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of a null-arm antibody that binds to TL1A, wherein the null-arm antibody comprises a null-arm TL1A antibody comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (Fab of TL1A), and the second heavy chain and the second light chain comprise a second Fab domain that contains a non-binding TL1A binding domain that does not specifically bind to a target (Fab of xTL1A), wherein the first and second light chains are identical, and the polynucleotide comprises one or more of the nucleic acid sequences of the insert of the plasmid deposited with the ATCC under accession number PTA-127347, the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127348, and the nucleic acid sequence of the insert of the plasmid deposited with the ATCC under accession number PTA-127351, a polynucleotide is provided.

[0222] In some aspects, an isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40 (iii) The sequence of TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 228, and the sequence of TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 229; and, (iv) The sequence of p40-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 238, and the sequence of p40-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 239; A polynucleotide is provided that contains

[0223] In some aspects, an isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) The sequence of a polypeptide having TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 234, and the sequence of a polypeptide having TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 235; and, (ii) The sequence of p40-HC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 236, and the sequence of p40-LC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 237; A polynucleotide is provided that contains

[0224] In some aspects, an isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) The sequence of TL1A-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127347, and the sequence of TL1A-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127348; and, (ii) The sequence of p40-VH encoded by the plasmid deposited with the ATCC under accession number PTA-127206, and the sequence of p40-VL encoded by the plasmid deposited with the ATCC under accession number PTA-127205 There is provided a polynucleotide containing

[0225] In some aspects, an isolated polynucleotide encoding one or more of the first, second, third, and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) a polypeptide sequence having TL1A-VH encoded by a plasmid deposited with the ATCC under accession number PTA-127350, and a polypeptide sequence having TL1A-VL encoded by a plasmid deposited with the ATCC under accession number PTA-127349; and (ii) the sequence of p40-HC encoded by a plasmid deposited with the ATCC under accession number PTA-127346, and the sequence of p40-LC encoded by a plasmid deposited with the ATCC under accession number PTA-127203 There is provided a polynucleotide containing

[0226] In some aspects, there is provided an isolated polynucleotide encoding the VH domain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 228. In some aspects, there is provided an isolated polynucleotide encoding the VL domain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 229. In some aspects, there is provided an isolated polynucleotide encoding the VH domain of a TL1A antibody engineered to abrogate TL1A binding, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 230. In some aspects, there is provided an isolated polynucleotide encoding the HC of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 231. In some aspects, there is provided an isolated polynucleotide encoding the HC of a TL1A antibody engineered to abrogate TL1A binding, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 232. In some aspects, there is provided an isolated polynucleotide encoding the LC of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 233. In some aspects, there is provided an isolated polynucleotide encoding the mFd chain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 234. In some aspects, there is provided an isolated polynucleotide encoding the LC-Fc chain of a TL1A antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 235. In some aspects, there is provided an isolated polynucleotide encoding the HC of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 236. In some aspects, there is provided an isolated polynucleotide encoding the LC of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 237. In some aspects, there is provided an isolated polynucleotide encoding the VH of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 238. In some aspects, there is provided an isolated polynucleotide encoding the VL of a p40 antibody, the polynucleotide containing the nucleic acid sequence set forth in SEQ ID NO: 239.

[0227] In some aspects, vectors are provided that contain one or more of the polynucleotides provided in the specification.

[0228] In some aspects, isolated host cells are provided that contain one or more of the polynucleotides provided in the specification, or the vectors provided in the specification.

[0229] In some aspects, methods are provided for producing an isolated antibody, the method containing the steps of culturing a host cell provided in the specification under conditions in which the antibody is produced, and recovering the antibody.

[0230] In some aspects, pharmaceutical compositions are provided that contain a therapeutically effective amount of an antibody provided in the specification and a pharmaceutically acceptable carrier.

[0231] As a result of the degeneracy of the genetic code, those skilled in the art will recognize that there are many nucleotide sequences that encode the polypeptides described in the specification. Some of these polynucleotides have minimal homology to the nucleotide sequences of the native genes. Nevertheless, polynucleotides that vary due to differences in codon usage frequency are specifically contemplated by the present invention. In addition, alleles of the genes containing the polynucleotide sequences provided in the specification are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations in nucleotides, such as deletions, additions, or substitutions. The resulting mRNA and proteins may or may not have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification, or database sequence comparison).

[0232] In one aspect, the VH and VL domains, or the full-length HC or LC, are encoded by separate polynucleotides. Alternatively, the VH and VL, or the HC and LC, are encoded by a single polynucleotide.

[0233] Polynucleotides complementary to such sequences are also encompassed by the present disclosure. The polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. Examples of RNA molecules include HnRNA molecules that contain introns and correspond to DNA molecules in a one-to-one manner, and mRNA molecules that do not contain introns. Additional coding or non-coding sequences are not necessary, but may be present within the polynucleotides of the present disclosure, and the polynucleotides may optionally be linked to other molecules or support materials.

[0234] The polynucleotides of the present invention can be obtained using chemical synthesis, recombinant methods or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of ordinary skill in the art can generate the desired DNA sequence using the sequences provided herein and commercially available DNA synthesizers.

[0235] To produce polynucleotides by recombinant methods, a polynucleotide containing the desired sequence can be inserted into a suitable vector, which can then be introduced into a suitable host cell for replication and amplification, as further discussed herein. The polynucleotide may be inserted into the host cell by means known in the art. The cell is transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F-mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained intracellularly as a non-integrating vector (such as a plasmid) or can be integrated into the host cell genome.

[0236] Suitable cloning vectors may be constructed according to standard techniques or selected from among the numerous cloning vectors available in the art. The cloning vector selected may vary according to the host cell intended to be used, but useful cloning vectors generally have one or more characteristics such as i) the ability to self-replicate, ii) a single target for a particular restriction endonuclease, or iii) a gene for a marker that can be used to select clones containing the vector. Suitable examples include plasmids and bacteriophages such as pUC18, pUC19, Bluescript (e.g. pBS SK+), and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial suppliers such as BioRad, Strategene, and Invitrogen.

[0237] Expression vectors are further provided. An expression vector is generally a replicable polynucleotide construct containing a polynucleotide according to the present disclosure. It is contemplated that the expression vector must be replicable in the host cell, either as an episome or as an integral part of the chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, adenoviruses, adeno-associated viruses, viral vectors including retroviruses, cosmids, and the expression vectors disclosed in WO 87 / 04462. The components of the vector generally include, but are not limited to, the following: a signal sequence; an origin of replication; one or more marker genes; and optionally one or more suitable transcriptional control elements (such as a promoter, enhancer, and terminator). For expression (i.e., translation), one or more translational control elements such as a ribosome binding site, a translation initiation site, and a stop codon are also usually required.

[0238] Vectors containing the polynucleotide of interest can be introduced into host cells by suitable means including electroporation, transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran or other substances; particle bombardment; lipofection; and infection (e.g., when the vector is an infectious pathogen such as vaccinia virus). The choice of introducing the vector or polynucleotide often depends on the characteristics of the host cell.

[0239] The present invention also provides host cells containing the polynucleotides described herein. Host cells capable of overexpressing heterologous DNA can be used for the purpose of isolating genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa and CHO cells. See also WO 87 / 04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or Bacillus subtilis) and yeasts (such as S. cerevisiae, S. pombe or K. lactis).

[0240] In addition, a number of commercially available cell lines and non-commercially available cell lines that express polypeptides or proteins may be utilized in accordance with the present invention. Those skilled in the art will recognize that different cell lines may have different nutritional requirements or may require different culture conditions for optimal growth and polypeptide or protein expression, and can modify the conditions as needed.

[0241] Pharmaceutical composition In another aspect, the present invention contains a pharmaceutical composition.

[0242] "Pharmaceutical composition" refers to a mixture of the antibody of the present invention and one or more excipients. As used herein, the pharmaceutical composition may contain one or more antibodies that bind to TL1A and / or TL1A and p40, or one or more polynucleotides encoding one or more of these antibodies. These compositions are well known in the art and may further contain suitable excipients such as pharmaceutically acceptable excipients including buffers.

[0243] The pharmaceutical compositions of the present invention may be in various forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and liquid, semi-solid and solid dosage forms such as lyophilized powders. The form depends on the intended method of administration and therapeutic use.

[0244] Other excipients and methods of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention may be manufactured by techniques well known in the pharmaceutical industry such as effective formulation and control procedures. The above considerations regarding effective formulation and control procedures are well known in the art and are described in standard texts. The formulation of drugs is discussed, for example, in Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980 and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0245] Excipients that are acceptable are buffers such as phosphates, citrates, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g. Zn-protein complexes); or may contain nonionic surfactants such as TWEEN®, PLURONIC® or polyethylene glycol (PEG).

[0246] The invention provided in this specification further encompasses methods and compositions for the treatment, prevention or management of one or more disorders or diseases selected from the group consisting of TL1A-related disorders, p40-related disorders, TL1A and p40-related disorders, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis and vasculitis.

[0247] In one aspect, the invention provides a method of treating a condition associated with one or more of TL1A and p40 expression in a subject. In some embodiments, the method of treating a condition associated with one or more of TL1A and p40 expression in a subject comprises administering to a subject in need thereof an effective amount of a composition (e.g., a pharmaceutical composition) comprising an individual anti-TL1A, anti-p40 or TL1A / p40 multispecific antibody described herein. Conditions associated with TL1A and p40 expression include, but are not limited to, abnormal expression of one or more of TL1A and p40 expression, altered or abnormal TL1A or p40 expression.

[0248] In one aspect, the present invention provides one or more selected from the group consisting of the anti-TL1A, anti-p40 and anti-TL1A / p40 antibodies described in the specification, or pharmaceutical compositions containing such antibodies, for use in therapy. In certain embodiments, the present invention also provides one or more of anti-TL1A, anti-p40, anti-TL1A / p40 antibodies for use in the treatment of disorders associated with one or more of TL1A- and p40-related disorders.

[0249] The present invention further provides one or more selected from the group consisting of the anti-TL1A, anti-p40 and anti-TL1A / p40 antibodies described in the specification, or pharmaceutical compositions containing such antibodies, for use in the manufacture of a medicament for use in therapy. In some embodiments, the therapy is the treatment of a disorder associated with one or more of TL1A, p40 and TL1A / p40.

[0250] Therapeutic method, diagnostic method and other methods The antibodies and antibody conjugates of the present invention are useful for a variety of applications including, but not limited to, methods of treatment and methods of diagnosis.

[0251] The TL1A antibody of the present invention may inhibit the activity of TL1A and may be useful in the treatment, prevention, suppression and improvement of TL1A-related diseases. The present invention provides a method for treating disorders associated with TL1A expression. The present invention relates to, in a subject, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczema-like dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, defecation and urination disorders, uveitis and vasculitis, and provides a method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition containing the TL1A antibody described in the specification. The preceding sentence provides a list of disorders associated with TL1A expression.

[0252] In some aspects, the TL1A antibody of the present invention may inhibit the activity of TL1A and may be useful in the treatment, prevention, suppression and improvement of one or more disorders selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behçet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczema-like dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, micturition and defecation disorders, uveitis and vasculitis. In some aspects, the TL1A antibody of the present invention may be useful in the treatment, prevention, suppression and improvement of asthma. In some aspects, the TL1A antibody of the present invention may be useful in the treatment, prevention, suppression and improvement of NASH.

[0253] In another aspect, the present invention further provides the antibody or pharmaceutical composition described in the specification for use in one or more methods of treating disorders associated with TL1A expression. The present invention also provides the use of the antibody described in the specification in the manufacture of a medicament for treating one or more disorders associated with TL1A expression. In another aspect, one or more methods of detecting, diagnosing or monitoring one or more disorders associated with TL1A expression are provided. For example, the anti-TL1A antibody described in the specification can be labeled with a detectable moiety such as a contrast agent and an enzyme-substrate label. The antibody described in the specification can also be used for in vivo diagnostic assays such as in vivo imaging (e.g., PET or SPECT), or as a staining reagent.

[0254] For all methods described in the specification, reference to an anti-TL1A antibody also includes a pharmaceutical composition containing the anti-TL1A antibody and one or more additional agents.

[0255] The TL1A / p40 antibodies of the present invention may inhibit the activity of TL1A and / or p40 and may be useful in the treatment, prevention, suppression, and amelioration of TL1A- and / or p40-related diseases. The present invention provides a method for treating disorders associated with TL1A expression. The present invention provides a method for treating one or more disorders selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behçet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthritis, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis, and vasculitis, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition containing the TL1A / p40 antibody described in the specification. The preceding sentence provides a list of disorders associated with TL1A / p40 expression.

[0256] In some aspects, the TL1A / p40 antibody of the present invention may inhibit the activity of TL1A and / or p40, and may be useful in the treatment, prevention, suppression and improvement of one or more disorders selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenosing Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthropathy, systemic erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis and vasculitis. In some aspects, the TL1A antibody of the present invention may be useful in the treatment, prevention, suppression and improvement of asthma. In some aspects, the TL1A / p40 antibody of the present invention may be useful in the treatment, prevention, suppression and improvement of NASH.

[0257] In another aspect, the present invention further provides the antibody or pharmaceutical composition described in the specification for use in one or more methods of treating disorders associated with TL1A and / or p40 expression. The present invention also provides the use of the antibody described in the specification in the manufacture of a medicament for treating one or more disorders associated with TL1A and / or p40 expression. In another aspect, one or more methods of detecting, diagnosing or monitoring one or more disorders associated with TL1A and / or p40 expression are provided. For example, the anti-TL1A / p40 antibody described in the specification can be labeled with a detectable moiety such as a contrast agent and an enzyme-substrate label. The antibody described in the specification can also be used for in vivo diagnostic assays such as in vivo imaging (e.g., PET or SPECT), or as a staining reagent.

[0258] With respect to all methods described in the specification, reference to an anti-TL1A / p40 antibody also includes a pharmaceutical composition containing the anti-TL1A / p40 antibody and one or more additional agents.

[0259] Administration and dosage The antibodies of the present invention are typically administered in an amount effective for the treatment in the state described in the specification. The antibodies of the present invention can be administered as the antibody itself or as a pharmaceutical composition containing the antibody.

[0260] The antibodies of the present invention are administered in a dosage effective for the intended treatment, in the form of a pharmaceutical composition adapted to such a route, by a suitable route.

[0261] In some embodiments, the antibody may be administered parenterally, for example, directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

[0262] In some aspects, the TL1A antibody of the present invention is administered subcutaneously. In some aspects, the TL1A / p40 antibody of the present invention is administered subcutaneously.

[0263] In another embodiment, the compounds of the present invention may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may also be administered directly to the eye or ear.

[0264] The dosage regimen for the antibody of the present invention or the composition containing said antibody is based on various factors including the type, age, weight, sex and medical condition of the subject; the severity of the condition; the route of administration; and the activity of the specific antibody used. Therefore, the dosage regimen may vary widely. In one aspect, the total daily dose of the antibody of the present invention is usually about 0.01 to about 100 mg / kg (i.e., mg of the antibody of the present invention per kg of body weight) for the treatment of the condition contemplated in the specification. In another aspect, the total daily dose of the antibody of the present invention is about 0.1 to about 50 mg / kg, and in another aspect, about 0.5 to about 30 mg / kg.

[0265] Co-administration The antibody of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides the uses, methods or compositions as defined in the specification, wherein the antibody of the present invention is used in combination with one or more other therapeutic agents contemplated in the specification.

[0266] "Combined" administration of two or more agents means that all of the agents are administered close enough in time so as to affect the treatment of the subject. Two or more agents may be administered simultaneously or sequentially. In addition, simultaneous administration may be effected by mixing the agents prior to administration or by administering the agents at the same time but as separate dosage forms, at the same or different sites of administration.

[0267] Various formulations of the antibodies of the present invention (e.g., one or more of anti-TL1A and anti-TL1A / p40 antibodies) may be used for administration. In some embodiments, the antibody may be administered as is. In some embodiments, the antibody and a pharmaceutically acceptable excipient may be in various formulations. Pharmaceutically acceptable excipients are known in the art and are relatively inert substances that facilitate the administration of pharmacologically active substances. For example, an excipient can provide form or robustness or can act as a diluent. Suitable excipients include, but are not limited to, stabilizers, wetting and emulsifying agents, salts for varying the osmolality, encapsulating agents, buffering agents, and skin penetration enhancers. Excipients and formulations for parenteral and oral drug delivery are shown in Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005.

[0268] In some embodiments, these agents are formulated for administration by injection (e.g., intraperitoneal, intravenous, subcutaneous, intramuscular, etc.). Thus, these agents can be combined with a pharmaceutically acceptable vehicle such as saline, Ringer's solution, dextrose solution, and the like. Specific dosing regimens, i.e., dosage, timing, and repetition, depend on the particular individual and the medical history of that individual.

[0269] The antibodies described in the specification (e.g., one or more of the TL1A and TL1A / p40 antibodies) can be administered by suitable methods including injection (e.g., intraperitoneal, intravenous, subcutaneous, intramuscular, etc.). Antibodies, e.g., monoclonal antibodies or multispecific antibodies, can also be administered via inhalation as described in the specification. Generally, for the administration of the antibodies of the present invention, the dosage depends on the host being treated and the particular method of administration. In one embodiment, the dosage of the antibodies of the present invention is from about 0.001 μg / kg body weight to about 20,000 μg / kg body weight. The term "body weight" is applicable when the patient is being treated. When isolated cells are being treated, "body weight" refers herein to "total cell body weight". The term "total body weight" may be used for application to the treatment of isolated cells and patients. All concentrations and treatment levels are represented in this application as "body weight" or simply "kg" and are considered to cover similar "total cell body weight" and "total body weight" concentrations. However, those skilled in the art will recognize the usefulness of various dosages, e.g., from 0.01 μg / kg body weight to 20,000 μg / kg body weight, from 0.02 μg / kg body weight to 15,000 μg / kg body weight, from 0.03 μg / kg body weight to 10,000 μg / kg body weight, from 0.04 μg / kg body weight to 5,000 μg / kg body weight, from 0.05 μg / kg body weight to 2,500 μg / kg body weight, from 0.06 μg / kg body weight to 1,000 μg / kg body weight, from 0.07 μg / kg body weight to 500 μg / kg body weight, from 0.08 μg / kg body weight to 400 μg / kg body weight, from 0.09 μg / kg body weight to 200 μg / kg body weight or from 0.1 μg / kg body weight to 100 μg / kg body weight.Furthermore, one of ordinary skill in the art will recognize that various different dosage levels can be utilized, for example, one or more selected from the group consisting of 0.0001 μg / kg, 0.0002 μg / kg, 0.0003 μg / kg, 0.0004 μg / kg, 0.005 μg / kg, 0.0007 μg / kg, 0.001 μg / kg, 0.1 μg / kg, 1.0 μg / kg, 1.5 μg / kg, 2.0 μg / kg, 5.0 μg / kg, 10.0 μg / kg, 15.0 μg / kg, 30.0 μg / kg, 50 μg / kg, 75 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 140 μg / kg, 150 μg / kg, 160 μg / kg, 180 μg / kg, 200 μg / kg, 225 μg / kg, 250 μg / kg, 275 μg / kg, 300 μg / kg, 325 μg / kg, 350 μg / kg, 375 μg / kg, 400 μg / kg, 450 μg / kg, 500 μg / kg, 550 μg / kg, 600 μg / kg, 700 μg / kg, 750 μg / kg, 800 μg / kg, 900 μg / kg, 1 μg / kg, 5 μg / kg, 10 μg / kg, 12 μg / kg, 15 mg / kg, 20 mg / kg, and 30 mg / kg. All of these dosages are representative, and dosages between these points are also expected to be utilized in the present invention. The above dosage ranges or dosage levels may be used for the antibodies of the present invention. For repeated administration over several days or longer, depending on the condition, the treatment is continued until the desired suppression of symptoms occurs or a sufficient therapeutic level is achieved.

[0270] Generally, for the administration of the antibodies provided in the specification, candidate dosages can be administered daily, weekly, bi-weekly, at 3-week intervals, 4-week intervals, 5-week intervals, 6-week intervals, 7-week intervals, 8-week intervals, 10-week intervals, 12-week intervals, or at intervals longer than 12 weeks.

[0271] In some embodiments, the candidate dosage is administered daily at a dosage of from about 1 μg / kg to up to 30 μg / kg, up to 300 μg / kg, up to 3 mg / kg, up to 30 mg / kg, up to 100 mg / kg or more, depending on the factors described above. For example, daily dosages of about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg and about 25 mg / kg may be used.

[0272] In some embodiments, the candidate dosage is administered weekly at a dosage of from about 1 μg / kg to up to 30 μg / kg, up to 300 μg / kg, up to 3 mg / kg, up to 30 mg / kg, up to 100 mg / kg or more, depending on the factors described above. For example, weekly dosages of about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg and about 30 mg / kg may be used.

[0273] In some embodiments, the candidate dosage is administered every two weeks at a dosage of from about 1 μg / kg to up to 30 μg / kg, up to 300 μg / kg, up to 3 mg / kg, up to 30 mg / kg, up to 100 mg / kg or more, depending on the factors described above. For example, two-week dosages of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg and about 30 mg / kg may be used.

[0274] In some embodiments, the candidate dosage is administered at a dosage of from about 1 μg / kg to up to 30 μg / kg, up to 300 μg / kg, up to 3 mg / kg, up to 30 mg / kg, up to 100 mg / kg, over a period of 3 weeks, depending on the factors described above. For example, 3-week dosages of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg may be used.

[0275] In some embodiments, the candidate dosage is administered at a dosage of from about 1 μg / kg to up to 30 μg / kg, up to 300 μg / kg, up to 3 mg / kg, up to 30 mg / kg, up to 100 mg / kg, over a period of 1 month or 4 weeks, depending on the factors described above. For example, 1-month dosages of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg may be used.

[0276] In other embodiments, the candidate dosage is administered daily at a dosage of from about 0.01 mg to up to about 1200 mg or more, depending on the factors listed above. For example, 1-day dosages of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg may be used.

[0277] In other embodiments, the candidate dosage is administered at a dosage of from about 0.01 mg to about 2000 mg or more per week, depending on the factors listed above. For example, a weekly dosage of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg or about 2000 mg may be used.

[0278] In other embodiments, the candidate dosage is administered at a dosage of from about 0.01 mg to about 2000 mg or more every two weeks, depending on the factors listed above. For example, a two-week dosage of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg or about 2000 mg may be used.

[0279] In other embodiments, the candidate dosage is administered at a dosage of from about 0.01 mg to about 2500 mg or more every three weeks, depending on the factors listed above. For example, a three-week dosage of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg or about 2500 mg may be used.

[0280] In other embodiments, the candidate dosage is administered at a dosage of from about 0.01 mg to about 3000 mg or more, every 4 weeks or 1 month, depending on the factors listed above. For example, a monthly dosage of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg or about 3000 mg may be used.

[0281] Other dosing regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. In one embodiment, the antibodies of the invention are administered with an initial prime dose followed by higher and / or continuous, substantially constant dosages. In some embodiments, dosing 1 to 4 times per week is contemplated. In other embodiments, dosing once a month or every other month or once every three months is contemplated. The progress of this therapy is readily monitored by conventional techniques and assays. The dosing regimen can be changed over time.

[0282] For the purposes of the present invention, the appropriate dosage of an antibody (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) depends on the antibody or composition thereof being used, the type and severity of the condition being treated, whether the agent is being administered for therapeutic purposes, the treatment history, the patient's medical history and response to the agent, the clearance rate of the patient for the administered agent, and the discretion of the attending physician. The clinician will typically administer the antibody until a dosage is reached that achieves the desired result. The dosage and / or frequency can be varied over the course of the treatment. Empirical considerations such as half-life generally contribute to the determination of dosage. For example, antibodies compatible with the human immune system, such as humanized or fully human antibodies, may be used to extend the half-life of the antibody and to prevent the antibody from being attacked by the host immune system. The frequency of administration may be determined and adjusted over the course of the treatment and is generally, but not necessarily, based on the treatment, suppression, amelioration, and / or delay of symptoms. Alternatively, a sustained release formulation of the antibody may be appropriate. A variety of formulations and devices for achieving sustained release are known in the art.

[0283] In certain embodiments, the dosage for an antibody (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) may be determined empirically in an individual who has received one or more administrations of the antibody. The individual is given a gradually increasing dosage of the antibody. To evaluate efficacy, one can follow the indicators of the disease.

[0284] In some embodiments, the antibodies provided in the specification (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) may be administered to a subject who has previously received one or more antibodies selected from the group consisting of TL1A and TL1A / p40 antibody therapeutics for the treatment of a disease. In some embodiments, the antibodies provided in the specification may be administered to a subject who has previously received an antibody selected from the group consisting of TL1A and TL1A / p40 antibody therapeutics for the treatment of a disease and where the previous TL1A or TL1A / p40 antibody therapeutic was of limited efficacy or had no efficacy in the subject (e.g., the subject's disease is resistant to treatment with the previous therapeutic).

[0285] Administration of the antibody according to the method of the present invention can be continuous or intermittent, depending, for example, on the physiological state of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to those skilled in the art. Administration of the antibody may be essentially continuous over a preselected period of time or may be a series of spaced dosages.

[0286] Therapeutic formulations of the antibody to be used in accordance with this invention are prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing an antibody having the desired degree of purity with a pharmaceutically acceptable carrier, excipient or stabilizer (Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005). Acceptable carriers, excipients or stabilizers are buffers such as phosphates, citrates and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzetonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONIC® or polyethylene glycol (PEG).

[0287] Kit Another aspect of the present invention provides a kit containing the antibody of the present invention or a pharmaceutical composition containing the antibody. The kit may include a diagnostic agent or a therapeutic agent in addition to the antibody of the present invention or its pharmaceutical composition. The kit may also include instructions for use in a diagnostic method or a therapeutic method. In some embodiments, the kit includes an antibody or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit includes an antibody or its pharmaceutical composition and one or more therapeutic agents.

[0288] A further aspect of the present invention is a kit containing one or more selected from the group consisting of TL1A and TL1A / p40 antibodies disclosed hereinabove, and instructions for use according to the methods of the invention described in the specification. Generally, these instructions contain instructions for one or more administrations selected from the group consisting of TL1A and TL1A / p40 antibodies for the above treatment.

[0289] In yet another aspect, the present invention contains a kit suitable for the treatment methods described in the specification. In one embodiment, the kit contains a first dosage form containing one or more antibodies of the present invention in an amount sufficient to perform the method of the present invention. In another embodiment, the kit contains one or more antibodies of the present invention in an amount sufficient to perform the method of the present invention, and a first container for at least a first dosage and a second container for a second dosage.

[0290] Some aspects of the pharmaceutical compositions, prophylactic agents or therapeutic agents of the present invention are preferably tested in vitro in a cell culture system and in an animal model organism such as a rodent animal model system for the desired therapeutic activity prior to use in humans.

[0291] The toxicity and efficacy of the prophylactic and / or therapeutic protocols of the present invention are, for example, LD 50 (the dose lethal to 50% of the population) and ED 50(The therapeutically effective dose for 50% of the population) may be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which may be expressed as the ratio LD 50 / ED 50 . Preventive and / or therapeutic agents that exhibit a high therapeutic index are preferred.

[0292] Furthermore, assays known to those of ordinary skill in the art may be used to evaluate the prophylactic and / or therapeutic utility of the treatment methods or combination therapies disclosed in the specification for treating or preventing cancer.

[0293] Instructions regarding one or more uses selected from the group consisting of the TL1A and TL1A / p40 antibodies described in the specification generally include information about the dosage, dosing schedule, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., multi-dose package), or sub-unit dose. Instructions supplied with the kits of the present invention are usually written instructions on a label or package insert (e.g., a paper sheet included in the kit), although machine-readable instructions (e.g., instructions held on a magnetic or optical storage disk) are also acceptable.

[0294] The kit of the present invention is in a suitable package. Suitable packages include, but are not limited to, vials, ampoules, tubes, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), etc. for each pharmaceutical composition and other included reagents for use upon administration to the subject of the pharmaceutical composition, such as buffers, balanced salt solutions, etc. Packaging for use in combination with specific devices such as inhalers, nasal administration devices (e.g., nebulizers), or infusion devices such as minipumps is also contemplated. The kit may have a sterile access port (e.g., the container may be an intravenous fluid bag or vial having a stopper penetrable by a hypodermic needle). The container may also have a sterile access port (e.g., the container may be an intravenous fluid bag or vial having a stopper penetrable by a hypodermic needle). At least one active agent in the composition is selected from the group consisting of TL1A and TL1A / p40 antibodies. The container may further contain a second pharmaceutically active agent.

[0295] Typically, the kit contains a container and a label or package insert on or associated with the container.

[0296] The contents of U.S. Provisional Patent Application Nos. 62 / 949,120 (filed December 17, 2019) and 63 / 110,693 (filed November 6, 2020) are hereby incorporated by reference for all purposes.

[0297] As used herein, the term "mammalian cell" includes reference to cells derived from a mammal, including human, rat, mouse, hamster, guinea pig, chimpanzee, or macaque. The cells may be cultured in vivo or in vitro.

[0298] As used herein, the term "purified product" refers to a preparation of a product isolated from the cellular components with which the product is normally associated or from other types of cells that may be present in the sample of interest.

[0299] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free of contaminants), more preferably at least 90% pure, more preferably at least 95% pure, even more preferably at least 98% pure, and most preferably at least 99% pure.

[0300] As used herein, the term "non-human animal" includes all non-human vertebrates, such as non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, mice, rats, rabbits or goats, etc., including non-human mammals and non-mammals, unless otherwise stated.

[0301] As used herein, the term "pharmaceutically acceptable" refers to a product or compound that has been approved (or is approvable) by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals including humans.

[0302] As used herein, the term "pharmaceutically acceptable excipient, carrier or adjuvant" or "acceptable pharmaceutical carrier" refers to an excipient, carrier or adjuvant that can be administered to a subject together with at least one antibody of the present disclosure and does not destroy the activity of the antibody. The excipient, carrier or adjuvant should not be toxic when administered with the antibody in a dosage sufficient to deliver a therapeutic effect.

[0303] As used herein, the term "amelioration" means a reduction or improvement of one or more symptoms as compared to the case where the antibody molecule of the present invention is not administered. "Amelioration" also includes shortening or reducing the duration of the symptoms.

[0304] As used herein, the term "prevention" refers to the prevention of the recurrence or onset of one or more symptoms of a disorder in a subject as a result of the administration of a prophylactic or therapeutic agent.

[0305] Efficacy is a measure of the activity of a therapeutic agent, expressed in terms of the amount required to produce an effect of a given intensity. A very potent drug produces a greater response at a lower concentration compared to a less potent drug that produces a smaller response at a lower concentration. Efficacy is a function of affinity and effectiveness. Effectiveness refers to the ability of a therapeutic agent to produce a biological response upon binding to a target ligand and the quantitative magnitude of this response.

[0306] Biological deposit Representative materials of this invention were deposited on December 17, 2021, with the American Type Culture Collection, 10801 University Boulevard, Manassas, VA 20110-2209, USA.

[0307] The vector "SFab p40-LC" with ATCC deposit number PTA-127203 contains a DNA insert encoding "SFab p40-LC" that includes the sequence shown in SEQ ID NO: 178. In this specification, SFab p40-LC is also referred to as "p40-LC". The vector "p40-0003 VL" with ATCC deposit number PTA-127205 contains a DNA insert encoding "p40-0003 VL" that includes the sequence shown in SEQ ID NO: 177. In this specification, "p40-0003 VL" is referred to as "p40 VL". The vector "p40-0003 VH" with ATCC deposit number PTA-127206 contains a DNA insert encoding "p40-0003 VH" that includes the sequence shown in SEQ ID NO: 171. In this specification, "p40-0003 VH" is referred to as "p40 VH". The vector "p40-HC" with ATCC deposit number PTA-127346 contains a DNA insert encoding "p40-HC" that includes the sequence shown in SEQ ID NO: 203. The vector "TL1A-0260-HC" with ATCC deposit number PTA-127347 contains a DNA insert encoding "TL1A-0260-HC" that includes the sequence shown in SEQ ID NO: 161. In this specification, "TL1A-0260-HC" is also referred to as "TL1A HC (functional)". The vector "TL1A-LC" with ATCC deposit number PTA-127348 contains a DNA insert encoding "TL1A-LC" that includes the sequence shown in SEQ ID NO: 19. The vector "TL1A-LC-Fc" with ATCC deposit number PTA-127349 contains a DNA insert encoding "TL1A-LC-Fc" that includes the sequence shown in SEQ ID NO: 205. The vector "TL1AmFd" with ATCC deposit number PTA-127350 contains a DNA insert encoding "TL1AmFd" that includes the sequence shown in SEQ ID NO: 207. The vector "[xTL1A]-0349-HC" with ATCC deposit number PTA-127351 contains a DNA insert encoding "[xTL1A]-0349-HC" that includes the sequence shown in SEQ ID NO: 166. It contains a DNA insert encoding "[xTL1A]-0349-HC" that includes the sequence shown in SEQ ID NO: 166.

[0308]

Table A

[0309] The deposit was made in accordance with the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and its Regulations (Budapest Treaty). As a result, the viability of the deposited material is maintained for 30 years from the date of deposit. The deposited material will be made available by the ATCC under a contract between Pfizer Inc. and the ATCC based on the terms of the Budapest Treaty, which guarantees that descendants of the deposited material will be generally available permanently and without restriction at the earlier of the issuance of the relevant U.S. patent or the publication of a U.S. or foreign patent application, and will be made available to persons determined by the Commissioner of the U.S. Patent and Trademark Office to have the right under 35 U.S.C. § 122 and the Commissioner's regulations (including 37 C.F.R. § 1.14, see particularly 886 OG 638).

[0310] The assignee of this application agrees to immediately replace the deposited material with another identical one upon notice if the culture of the deposited material dies, or is lost, or is destroyed when cultured under suitable conditions. The availability of the deposited material should not be construed as a license to practice the invention in violation of rights granted under the patent laws of a government under its authority.

[0311] Materials and methods A variety of techniques for the generation of antibodies are described, including conventional hybridoma methods for producing monoclonal antibodies, recombinant techniques for producing antibodies (including chimeric antibodies, e.g., humanized antibodies), antibody production in transgenic animals, and more recent phage display techniques for producing "fully human" antibodies.

[0312] A method for producing the antibodies provided in the specification is provided in this specification. The antibodies of the present invention can be produced by procedures known in the art. The polypeptide can be generated by proteolysis or other degradation of the antibody, by the above recombinant methods (i.e., single or fusion polypeptides), or by chemical synthesis. Polypeptides of the antibody, particularly shorter polypeptides up to about 50 amino acids, are conveniently produced by chemical synthesis. Methods of chemical synthesis are known in the art and commercially available. For example, antibodies can be produced on an automated polypeptide synthesizer by solid-phase methods. See also U.S. Patent Nos. 5,807,715, 4,816,567, and 6,331,415.

[0313] (e.g., depending on the characteristics and components of the antibody) Suitable methods may be used to produce the multispecific antibodies provided in the specification.

[0314] One approach for producing multispecific antibodies is to fuse antibody variable domains having the desired binding specificities to the sequences of immunoglobulin constant regions. Preferably, it is fused to an immunoglobulin heavy chain constant region having at least a portion of the hinge, CH2, and CH3 regions. In some embodiments, a first heavy chain constant region (CH1) having a site for light chain binding can be present in at least one of the fusions. In some embodiments, the polynucleotides encoding the immunoglobulin heavy chain fusions and optionally the immunoglobulin light chains may be inserted into different expression vectors and co-transfected into a suitable host organism. In other embodiments, the coding sequences for all two or three polypeptide chains may be inserted into one expression vector if expression in equal ratios of at least two polypeptide chains results in high yields or if the ratio is not particularly critical.

[0315] In one approach, the multispecific antibody is composed of a first binding specificity in one arm and a hybrid immunoglobulin heavy chain having a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure, having immunoglobulin light chains only in half of the multispecific molecule, facilitates separation of the desired multispecific compound from unwanted combinations of immunoglobulin chains. This approach is described in WO 94 / 04690.

[0316] In another approach, the multispecific antibody is composed of amino acid modifications in the first hinge region of one arm, where the substituted amino acids in the first hinge region have opposite charges to the corresponding amino acids in the second hinge region of the other arm. This approach is described in International Patent Application No. PCT / US2011 / 036419 (published as WO 2011 / 143545).

[0317] In another approach, the formation of a desired heteromultimeric or heterodimeric protein (e.g., bispecific antibody) is enhanced by altering or engineering the interface between the first and second Fc chains. In this approach, the multispecific antibody may be composed of CH3 regions, which contain a first CH3 polypeptide and a second CH3 polypeptide that interact together to form a CH3 interface, and one or more amino acids within the CH3 interface destabilize homodimer formation and are not electrostatically unfavorable for homodimer formation. This approach is described in International Patent Application No. PCT / US2011 / 036419 (International Publication No. 2011 / 143545). In some embodiments, one Fc chain of the bispecific antibody can contain amino acid modifications at positions 223 and 228 in the hinge region of human IgG2 (e.g., C223E or C223R, and P228E or P228R), and position 409 in the CH3 region (e.g., K409R (EU numbering scheme)), and the other Fc chain of the bispecific antibody can contain amino acid modifications at positions 223, 225, and 228 in the hinge region of human IgG2 (e.g., C223E or C223R, E225R, and P228E or P228R), and position 368 in the CH3 region (e.g., L368E (EU numbering scheme)). In other embodiments, one Fc chain of the bispecific antibody can contain amino acid modifications at positions 223 and 228 in the hinge region of human IgG2 (e.g., C223E or C223R, and P228E or P228R), and position 368 in the CH3 region (e.g., L368E (EU numbering scheme)), and the other Fc chain of the bispecific antibody can contain amino acid modifications at positions 223, 225, and 228 in the hinge region of human IgG2 (e.g., C223E or C223R, E225R, and P228E or P228R), and position 409 in the CH3 region (e.g., K409R (EU numbering scheme)). In some embodiments, the bispecific antibody can contain amino acid modifications at positions 221 and 228 in the hinge region of human IgG1 (e.g., D221R or D221E, and P228R or P228E), and position 409 or 368 in the CH3 region (e.g., K409R or L368E (EU numbering scheme)).In some embodiments, the bispecific antibody can contain amino acid modifications at position 228 (e.g., P228E or P228R) in the hinge region of human IgG4, and at position 409 or 368 (e.g., R409 or L368E (EU numbering scheme)) in the CH3 region.

[0318] In some embodiments, the multispecific antibody may have a knob-in-hole mutation in the Fc chain. For example, in some embodiments, in a bispecific antibody having a knob-in-hole mutation, the first Fc chain of the antibody Fc domain has one or more mutations for forming a "knob", and the second Fc chain of the antibody Fc domain has one or more mutations for forming a "hole" (and vice versa). Representative antibody knob-in-hole manipulations are described in U.S. Patent No. 5,731,168, International Publication No. 2009 / 089004, U.S. Patent Application Publication No. 2009 / 0182127, Marvin and Zhu, Acta Pharmacologica Sincia (2005) 26(6):649-658, and Kontermann (2005) Acta Pharacol. Sin., 26:1-9.

[0319] "Knob" refers to at least one amino acid side chain that protrudes from the interface of a first polypeptide (e.g., a first Fc chain) and can thus be positioned in a complementary hole in an adjacent second polypeptide (e.g., a second Fc chain), thereby favoring heterodimer formation over homodimer formation. The knob may be present at the original interface or may be introduced synthetically (e.g., by altering the nucleic acid encoding the interface). Usually, the nucleic acid encoding the interface of the first polypeptide is altered to encode a knob. To achieve this, the nucleic acid encoding at least one original amino acid residue of the first polypeptide is replaced with a nucleic acid encoding at least one "import" amino acid residue having a larger side chain volume than the original amino acid residue. Some import residues for knob formation are generally naturally occurring amino acid residues, preferably selected from arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W).

[0320] "Hole" refers to at least one amino acid side chain that is recessed from the interface of a second polypeptide (e.g., a second Fc chain) and thus accommodates a corresponding knob in an adjacent first polypeptide (e.g., a first Fc chain). The hole may be present at the original interface or may be introduced synthetically (e.g., by altering the nucleic acid encoding the interface). Usually, the nucleic acid encoding the interface of the second polypeptide is altered to encode a hole. To achieve this, the nucleic acid encoding at least one original amino acid residue of the second polypeptide is replaced with a DNA encoding at least one "import" amino acid residue having a smaller side chain volume than the original amino acid residue. Some import residues for hole formation are usually naturally occurring amino acid residues, preferably selected from alanine (A), serine (S), threonine (T), and valine (V).

[0321] As used herein, the term "interface" generally refers to amino acid residues present in domains that can participate in the contact of a first polypeptide and a second polypeptide. An "original amino acid" residue is one that is replaced by an "import amino acid" residue, which may have a side chain volume smaller or larger than that of the original residue. The import amino acid residue may be a naturally occurring amino acid residue or a non-naturally occurring amino acid residue, but preferably the former. A "naturally occurring" amino acid residue is a residue encoded by the genetic code. A "non-naturally occurring" amino acid residue means a residue that is not encoded by the genetic code but can covalently bond with adjacent amino acid residues in a polypeptide chain. Examples of non-naturally occurring amino acid residues are norleucine, ornithine, norvaline, homoserine, and other amino acid residue analogs described in Ellman et al., Meth. Enzym. 202:301-336 (1991).

[0322] Once a nucleic acid sequence encoding the molecule of the present invention (i.e., the binding domain) is obtained, a vector for the production of the molecule may be generated by recombinant DNA techniques using techniques well known in the art.

[0323] The polynucleotide encoding the antibody (binding domain) of the present invention may include an expression control polynucleotide sequence operably linked to the antibody coding sequence, including a naturally associated or heterologous promoter region known in the art. The expression control sequence may be a eukaryotic promoter system in a vector capable of transforming or transfecting eukaryotic host cells, but control sequences for prokaryotic hosts may also be used. Once the vector is incorporated into a suitable host cell line, the host cell is caused to express the nucleotide sequence and, if desired, to grow under conditions suitable for the collection and purification of the antibody. Examples of eukaryotic cell lines include CHO cell lines, various COS cell lines, HeLa cells, myeloma cell lines, transformed B cells, or human fetal kidney cell lines.

[0324] In one aspect, the DNA encoding the antibody of the present invention is isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody). Once isolated, the DNA may be placed in an expression vector, which is then transfected into host cells such as monkey COS cells, CHO cells or myeloma cells that would otherwise not produce immunoglobulin protein to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA may also be modified, for example, to improve one or more properties (e.g., binding affinity, immunogenicity, etc.) of the corresponding antibody.

[0325] In one aspect, the present invention provides a method for manufacturing the polynucleotides described in the specification. For example, the polynucleotides of the present invention can be obtained using chemical synthesis, recombinant methods or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail herein. One of ordinary skill in the art can generate the desired DNA sequence using the sequences provided herein and a commercially available DNA synthesizer.

[0326] To produce polynucleotides by recombinant methods, a polynucleotide containing the desired sequence can be inserted into a suitable vector, which can then be introduced into a suitable host cell for replication and amplification, as further discussed herein. The polynucleotide may be inserted into the host cell by means known in the art. The cell is transformed by introducing an exogenous polynucleotide by direct uptake, endocytosis, transfection, F mating or electroporation. Once introduced, the exogenous polynucleotide can be maintained intracellularly as a non-integrating vector (such as a plasmid) or can be integrated into the host cell genome. The polynucleotide amplified in this way can be isolated from the host cell by methods well known in the art (e.g., Sambrook et al., 1989).

[0327] Alternatively, PCR enables the reproduction of DNA sequences. The PCR technique is well known in the art and is described in U.S. Patent Nos. 4,683,195, 4,800,159, 4,754,065, and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

[0328] RNA can be obtained by using DNA isolated in a suitable vector and inserting it into a suitable host cell. The cells are replicated, and once the DNA has been transcribed into RNA, the RNA can then be isolated using methods well known to those skilled in the art, such as those described in Sambrook et al., 1989 (supra).

[0329] Suitable cloning vectors may be constructed according to standard techniques or selected from among the numerous cloning vectors available in the art. The cloning vector selected may vary according to the host cell intended to be used, but useful cloning vectors generally have the ability to self-replicate, may have a single target for a particular restriction endonuclease, or may have a gene for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacteriophage viruses, such as pUC18, pUC19, Bluescript (e.g., pBS SK+ ) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial suppliers such as BioRad, Strategene, and Invitrogen.

[0330] An expression vector is generally a replicable polynucleotide construct containing the polynucleotide according to the present invention. It is suggested that the expression vector must be replicable in the host cell, either as an episome or as an essential part of chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, adenoviruses, adeno-associated viruses, viral vectors including retroviruses, cosmids, and the expression vectors disclosed in WO 87 / 04462. The components of the vector generally include, but are not limited to, the following: a signal sequence, an origin of replication, one or more marker genes, and optionally one or more suitable transcriptional control elements (such as a promoter, an enhancer, and a terminator). For expression (i.e., translation), one or more translational control elements such as a ribosome binding site, a translation initiation site, and a stop codon are also usually required.

[0331] A vector containing the polynucleotide of interest can be introduced into a host cell by appropriate means including electroporation, transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran or other substances; particle guns; lipofection; and infection (e.g., when the vector is an infectious pathogen such as vaccinia virus). The choice of means for introducing the vector or polynucleotide often depends on the characteristics of the host cell.

[0332] Host cells capable of overexpressing heterologous DNA can be used for the purpose of expressing a gene encoding the antibody, polypeptide, or protein of interest. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa, and CHO cells. See WO 87 / 04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or Bacillus subtilis) and yeasts (such as S. cerevisiae, S. pombe, or K. lactis). Cells overexpressing the antibody or protein of interest can be identified by known screening methods.

[0333] In addition to the selection of host cells, factors that can affect glycosylation during the recombinant production of antibodies include growth mode, medium formulation, culture density, oxygenation, pH, purification scheme, and the like. Various methods have been proposed to alter the glycosylation patterns achieved in specific host organisms, including introducing or overexpressing certain enzymes involved in oligosaccharide production (U.S. Patent Nos. 5,047,335, 5,510,261, 5,278,299). Glycosylation or certain types of glycosylation can be enzymatically removed from glycoproteins, for example, using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3. In addition, recombinant host cells can be genetically engineered to be defective in the processing of certain types of polysaccharides. These and similar techniques are well known in the art.

[0334] Other methods of modification include, but are not limited to, using coupling techniques known in the art, including enzymatic means, oxidative substitution, and chelation. Modifications can be used, for example, for the attachment of labels for immunoassays. Modified polypeptides are produced by procedures established in the art and can be screened using standard assays known in the art, some of which are described below and in the examples.

[0335] In some aspects of the invention, the antibody contains a modified constant region, such as a constant region with increased affinity for human Fcγ receptors, and is immunologically inert or partially inert, e.g., does not induce complement-mediated lysis, does not stimulate antibody-dependent cell-mediated cytotoxicity (ADCC), or does not activate macrophages; or is reduced in activity (compared to the unmodified antibody) in one or more of the following: induction of complement-mediated lysis, stimulation of antibody-dependent cell-mediated cytotoxicity (ADCC), or activation of microglia. Different modifications of the constant region may be used to achieve an optimal level or combination of effector functions. See, for example, Morgan et al., Immunology 86:319-324, 1995; Lund et al., J. Immunology 157:4963-4969, 1996; Idusogie et al., J. Immunology 164:4178-4184, 2000; Tao et al., J. Immunology 143: 2595-2601, 1989 and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some aspects, the constant region is modified as described in Eur. J. Immunol., 29:2613-2624, 1999; International Patent Application No. PCT / GB99 / 01441 and / or UK Application No. 9809951.8. In other aspects, the constant region is aglycosylated for N-linked glycosylation. In some aspects, the constant region is aglycosylated for N-linked glycosylation by mutating glycosylated amino acid residues that are part of the N-glycosylation recognition sequence in the constant region or the flanking residues. For example, the N-glycosylation site N297 may be mutated to A, Q, K, or H. See also Tao et al., J. Immunology 143: 2595-2601, 1989 and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some aspects, the constant region is aglycosylated for N-linked glycosylation.The constant region may be aglycosylated for N-linked glycosylation, either enzymatically (such as removing carbohydrates by the enzyme PNGase) or by expression in a glycosylation-deficient host cell.

[0336] Other antibody modifications include antibodies modified as described in WO 99 / 58572. These antibodies contain an effector domain having an amino acid sequence substantially homologous to all or part of the constant region of a human immunoglobulin heavy chain, in addition to a binding domain directed to a target molecule. These antibodies can bind to a target molecule without inducing significant complement-dependent lysis or cell-mediated destruction of the target. In some embodiments, the effector domain can specifically bind to either or both of FcRn or FcγRIIb. These are typically based on chimeric domains derived from two or more human immunoglobulin heavy chain CH2 domains. Antibodies modified in this manner are particularly suitable for use in long-term antibody therapy to avoid inflammatory and other adverse reactions to conventional antibody therapies.

[0337] In some embodiments, the Fc chain of the antibodies provided in the specification may be modified to remove effector function. For example, the Fc chain of human IgG1 may be modified by introducing mutations L234A, L235A, and G237A using standard primer-directed PCR mutagenesis to remove effector function resulting from binding to FcγRIII, providing an effector function null phenotype (Canfield et al., J. Exp. Med (1991) 173: 1483-1491; Shields et al., J. Biol. Chem. (2001) 276:6591-604).

[0338] In some embodiments, the multispecific antibodies provided in the specification may be engineered to contain at least one cysteine residue that may interact with a corresponding cysteine residue on another polypeptide chain of the invention to form an interchain disulfide bond. The interchain disulfide bond may serve to stabilize the multispecific antibody, improve expression and recovery in a recombinant system, result in stable and consistent formation, and improve the in vivo stability of the isolated and / or purified product. One or more cysteine residues may be introduced into any part of the polypeptide chain, either as a single amino acid or as part of a larger amino acid sequence, such as part of a hinge region. In a specific aspect, at least one cysteine residue is engineered to be present at the C-terminus of the polypeptide chain.

[0339] The foregoing description and the following examples detail certain specific embodiments of the disclosure and illustrate the best mode contemplated by the inventors. However, no matter how detailed the foregoing may appear in text, it should be understood that the disclosure may be practiced in many ways and it will be appreciated that the disclosure should be construed in accordance with the claims and their equivalents.

[0340] The disclosed teachings have been described with respect to various uses, methods, kits, and compositions, and it will be appreciated that various changes and modifications can be made without departing from the teachings set forth herein and the disclosure described in the claims below. The following examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented in the specification. The teachings have been described with respect to these representative embodiments, and those skilled in the art will readily appreciate that numerous variations and modifications of these representative embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the teachings.

Examples

[0341] The following examples of specific aspects for carrying out the present invention are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0342] Example 1 Preparation of anti-TL1A antibody TL1A-0002 The heavy and light chain amino acid sequences of a fully human affinity-optimized anti-TL1A are set forth in SEQ ID NO: 228 and SEQ ID NO: 106 of U.S. Patent No. 9,683,998 (Arch et al., Pfizer Inc. and Bristol-Myers Squibb Company, June 19, 2017). 1 1D1 1.31 is a human IgG1 / κ neutralizing antibody having L(247)A, L(248)A, and G(250)A mutations (Pfabat numbering) in the fragment crystallizable region (Fc region) to minimize effector function, and is designated TL1A-0002 herein. The heavy and light chain amino acid sequences constituting TL1A-0002 are shown in SEQ ID NO: 10 and SEQ ID NO: 17, respectively. The TL1A-0002 antibody demonstrated efficacy in a Phase 2a trial for moderate to severe ulcerative colitis (UC), but among subjects with neutralizing antibodies, a high frequency of positive antidrug antibody (ADA) subjects, 41 out of 50 doses or 82%, and antidrug antibodies (ADA) occurred in 5 out of 50 doses or 10% (https: / / clinicaltrials.gov, Identification No. NCT02840721). The occurrence and maturation of neutralizing antidrug antibodies in patients limit the long-term benefit of the drug. We aimed to develop a good antibody that maintains the efficacy of TL1A-0002 while reducing the risk of immunogenicity to provide a low-ADA therapeutic.

[0343] Example 2 Derivatization of an anti-TL1A binding domain engineered to reduce immunogenicity and eliminate post-translational asparagine deamidation modifications For the fully human anti-TL1A antibody TL1A-0002, as a biotherapeutic for the long-term treatment of inflammatory bowel disease (IBD), operations were performed to reduce immunogenicity and remove post-translational asparagine deamidation modifications. The predicted immunogenicity of the amino acid sequence of TL1A-0002 was analyzed by two methods described below, and the predicted T cell epitopes were identified in silico. For any protocol, the sequences flagged with the rules described in the specification were regarded as epitopes. The sequences were subjected to EpiMatrix analysis of the ...

Claims

**Claim 1** An isolated antibody comprising a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site comprises a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), the second antigen-binding site comprises a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), the p40-binding domain comprises the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and the sequence of CDR-L3 shown in SEQ ID NO: 175; and the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and the sequence of CDR-H3 shown in SEQ ID NO: 169, the TL1A-binding domain comprises the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13, and (i) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (ii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (iii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 32; (iv) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (v) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (vi) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (vii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (viii) the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 35; (ix) the sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (x) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xi) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xii) The sequence of CDR-H1 shown in SEQ ID NO: 61; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xiii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 31; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xiv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 38; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xv) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xvi) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xvii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 46; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xviii) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xix) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 51; the sequence of CDR-H3 shown in SEQ ID NO: 35; (xx) The sequence of CDR-H1 shown in SEQ ID NO: 86; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; (xxi) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 41; the sequence of CDR-H3 shown in SEQ ID NO: 35; and, (xxii) The sequence of CDR-H1 shown in SEQ ID NO: 109; the sequence of CDR-H2 shown in SEQ ID NO: 56; the sequence of CDR-H3 shown in SEQ ID NO: 32; An antibody further comprising a combination of heavy chain CDRs selected from Claim 2 An isolated antibody comprising a first antigen-binding site that binds to TL1A and a second antigen-binding site that binds to p40, wherein the first antigen-binding site comprises a TL1A-binding heavy-chain variable region (TL1A-VH) and a TL1A-binding light-chain variable region (TL1A-VL), the second antigen-binding site comprises a p40-binding heavy-chain variable region (p40-VH) and a p40-binding light-chain variable region (p40-VL), and (i) the p40-binding domain comprises the sequence of CDR-L1 shown in SEQ ID NO: 173; the sequence of CDR-L2 shown in SEQ ID NO: 174; and the sequence of CDR-L3 shown in SEQ ID NO: 175; and the sequence of CDR-H1 shown in SEQ ID NO: 167; the sequence of CDR-H2 shown in SEQ ID NO: 168; and the sequence of CDR-H3 shown in SEQ ID NO: 169, and (ii) the TL1A-binding domain comprises the sequence of CDR-L1 shown in SEQ ID NO: 11; the sequence of CDR-L2 shown in SEQ ID NO: 12; and the sequence of CDR-L3 shown in SEQ ID NO: 13; and the sequence of CDR-H1 shown in SEQ ID NO: 30; the sequence of CDR-H2 shown in SEQ ID NO: 41; and the sequence of CDR-H3 shown in SEQ ID NO:

32. Antibody.

3. The antibody according to claim 1, comprising a framework sequence of TL1A-VH derived from a VH sequence of a human germline selected from the group consisting of IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, and a framework sequence of TL1A-VL derived from a VL sequence of a human germline selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01.

4. The anti-TL1A-VL contains the amino acid sequence shown in SEQ ID NO: 18, and the anti-TL1A-VH contains a sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO:

120. The antibody according to claim 1.

5. The antibody according to claim 1, containing the sequence of anti-TL1A-VH shown in SEQ ID NO: 42 and the sequence of anti-TL1A-VL shown in SEQ ID NO:

18.

6. The antibody according to claim 1, containing the sequence of anti-TL1A-VH encoded by the nucleic acid sequence shown in SEQ ID NO: 228 and the sequence of anti-TL1A-VL encoded by the nucleic acid sequence shown in SEQ ID NO:

229.

7. The antibody according to claim 1, containing the framework sequence of p40-VH derived from the VH sequence of the human germline selected from the group consisting of DP3, DP7, DP73, DP75, and DP88, and the framework sequence of p40-VL derived from the VL sequence of the human germline selected from the group consisting of DPK4, DPK5, DPK7, DPK8, and DPK9.

8. The antibody according to claim 1, wherein the p40-VL contains the amino acid sequence shown in SEQ ID NO: 177, and the p40-VH contains the amino acid sequence shown in SEQ ID NO:

171.

9. The antibody according to claim 1, containing the sequence of p40-VH encoded by the nucleic acid sequence shown in SEQ ID NO: 238 and the sequence of p40-VL encoded by the nucleic acid sequence shown in SEQ ID NO:

239.

10. The antibody according to claim 1, wherein the antibody contains the first, second, third, and fourth polypeptide chains, the first and third polypeptide chains together form the Fab of the TL1A, and the second and fourth polypeptide chains together form the Fab of the p40.

11. The first, second, third, and fourth polypeptide chains are (i) the sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (ii) The sequence of the first polypeptide is as shown in SEQ ID NO: 188, the sequence of the second polypeptide is as shown in SEQ ID NO: 186, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (iii) The sequence of the first polypeptide is as shown in SEQ ID NO: 192, the sequence of the second polypeptide is as shown in SEQ ID NO: 190, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; (iv) The sequence of the first polypeptide is as shown in SEQ ID NO: 194, the sequence of the second polypeptide is as shown in SEQ ID NO: 193, the sequence of the third polypeptide is as shown in SEQ ID NO: 19, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 178; and (v) The sequence of the first polypeptide is as shown in SEQ ID NO: 200, the sequence of the second polypeptide is as shown in SEQ ID NO: 196, the sequence of the third polypeptide is as shown in SEQ ID NO: 202, and the sequence of the fourth polypeptide is as shown in SEQ ID NO: 198; The antibody according to claim 10, having a combination of sequences according to any one of the groups selected from

12. The antibody according to claim 11, wherein the sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO:

178.

13. An isolated antibody that specifically binds to TL1A and p40, the antibody containing first, second, third, and fourth polypeptide chains, wherein the first and third polypeptide chains together form a TL1A binding region, the second and fourth polypeptide chains together form a p40 binding region, and the sequence of the first polypeptide is as shown in SEQ ID NO: 205, the sequence of the second polypeptide is as shown in SEQ ID NO: 203, the sequence of the third polypeptide is as shown in SEQ ID NO: 207, and the sequence of the fourth polypeptide is as shown in SEQ ID NO:

178.

14. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody contains first, second, third, and fourth polypeptide chains, the first and third polypeptide chains together form a TL1A binding region, the second and fourth polypeptide chains together form a p40 binding region, and the first polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127349, the second polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127346, the third polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127350, and the fourth polypeptide sequence contains a sequence encoded by a plasmid deposited with the ATCC under accession number PTA-127203.

15. The antibody according to claim 1, characterized in that the score in an affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) assay is less than 2.

16. The antibody according to claim 1, characterized in that at least 50% of the charge heterogeneity of the antibody is non-acidic and non-basic when measured by antibody imaging capillary electrophoresis (iCE) on a sample without stress to be evaluated (T0).

17. The antibody according to claim 1, wherein the antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM when measured by SPR, and / or the immobilized antibody binds to human p40 with a binding affinity of less than 1 nM when measured by SPR.

18. The antibody according to claim 1, wherein the antibody binds simultaneously to p40 (IL-23) and TL1A in an SPR assay, wherein the antibody is injected onto immobilized TL1A and the resulting complex is treated with IL-23.

19. The antibody according to claim 1, wherein the half-life of the antibody is at least 10 days in TG32 mice in a 2-week analysis, and / or the half-life of the antibody is at least 21 days in cynomolgus monkeys.

20. An antibody for use as a medicament, wherein said use is for one or more treatments selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrostenotic Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-responsive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative colitis, voiding and defecation disorders, uveitis and vasculitis, the antibody according to claim 1.

21. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to claim 1 and a pharmaceutically acceptable carrier.

22. An isolated polynucleotide comprising one or more nucleotide sequences encoding the antibody according to claim 1, or encoding one or more of the first, second, third and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) the sequence of TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 228, and the sequence of TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 229; and (ii) the sequence of p40-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 238, and the sequence of p40-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 239; A polynucleotide containing the same.

23. An isolated polynucleotide encoding one or more of the first, second, third and fourth polypeptides of an antibody that binds to both TL1A and p40, (i) The sequence of a polypeptide having TL1A-VH encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 234, and the sequence of a polypeptide having TL1A-VL encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 235; and, (ii) The sequence of p40-HC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 236, and the sequence of p40-LC encoded by a nucleic acid containing the nucleic acid sequence shown in SEQ ID NO: 237; A polynucleotide containing the same. **Claim 24** A vector containing the polynucleotide according to Claim 22. **Claim 25** An isolated host cell containing the vector according to Claim 24. **Claim 26** A method for producing an isolated antibody, the method comprising culturing the host cell according to Claim 25 under conditions in which the antibody is produced and recovering the antibody.

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